Microglia and Parkinson
Arimoto T, Bing G (2003) Up-regulation of inducible nitric
oxide synthase in the substantia nigra by lipopolysaccharide causes
Microglial
activation and neurodegeneration. Neurobiol.Dis. 12:35-45
Abstract:
The present study was designed to examine whether expression of iNOS
was involved in LPS-induced neurodegeneration in rat substantia
nigra (SN) and to study the role of NO in the loss of the SN
dopaminergic neurons. In Western blot analysis, iNOS was induced in
the SN after injection of LPS in a time- and dose-dependent manner.
Immunofluorescence and immunohistochemical analyses revealed that
the iNOS is located in a fully activated Microglia
with the characteristic amoeboid morphology. Furthermore,
LPS-induced loss of dopaminergic neurons was significantly inhibited
by the administration of L-N(G)-nitroarginine, a selective inhibitor
of NOS, and the glucocorticoid dexamethasone. These inhibiting
agents for iNOS reduced LPS-induced Microglial
activation, suggesting that NO has a role in inflammatory-mediated
Microglial
activation. These results demonstrate that LPS induces the
expression of iNOS in activated Microglia
in the SN, and that NO and/or its metabolites may play a crucial
role in inflammation-mediated degeneration of dopaminergic neurons
Asanuma M, Miyazaki I, Tsuji T, Ogawa N (2003) [New aspects
of neuroprotective effects of nonsteroidal anti-inflammatory drugs].
Nihon Shinkei Seishin Yakurigaku Zasshi 23:111-119
Abstract:
Nonsteroidal anti-inflammatory drugs (NSAIDs) exert
anti-inflammatory, analgesic and antipyretic activities and are
involved in the suppression of prostaglandin synthesis by inhibiting
cyclooxygenase (COX), a prostaglandin synthesizing enzyme. It has
been recently revealed that NSAIDs also possess inhibitory effects
on the generating system of nitric oxide radicals and modulating
effects on transcription factors and nuclear receptors which are
related to inflammatory reactions. Since it has been reported that
inflammatory processes are associated with the pathophysiology of
several neurodegenerative diseases and that NSAIDs inhibit amyloid
beta-protein-induced neurotoxicity to reduce the risk for
Alzheimer's disease, a number of studies have been conducted
focusing on the neuroprotective effects of NSAIDs. It has been
clarified that the drugs exert neuroprotective effects, which are
not related to their COX-inhibiting property, on pathophysiology of
various neurological disorders. In this article, new aspects of
neuroprotective effects of NSAIDs have been reviewed, especially, in
Alzheimer's disease and Parkinson's
disease, discussing various pharmacological effects of NSAIDs other
than their inhibitory action on COX
Beal MF (2003) Mitochondria, oxidative damage, and
inflammation in Parkinson's
disease. Ann.N.Y.Acad.Sci. 991:120-131
Abstract: The pathogenesis
of Parkinson's disease (PD)
remains obscure, but there is increasing evidence that impairment of
mitochondrial function, oxidative damage, and inflammation are
contributing factors. The present paper reviews the experimental and
clinical evidence implicating these processes in PD. There is
substantial evidence that there is a deficiency of complex I
activity of the mitochondrial electron transport chain in PD. There
is also evidence for increased numbers of activated Microglia
in both PD postmortem tissue as well as in animal models of PD.
Impaired mitochondrial function and activated Microglia
may both contribute to oxidative damage in PD. A number of therapies
targeting inflammation and mitochondrial dysfunction are efficacious
in the MPTP model of PD. Of these, coenzyme Q(10) appears to be
particularly promising based on the results of a recent phase 2
clinical trial in which it significantly slowed the progression of
PD
Cardenas H, Bolin LM (2003) Compromised reactive microgliosis
in MPTP-lesioned IL-6 KO mice. Brain Res. 985:89-97
Abstract:
Reactive gliosis, the cellular manifestation of neuroinflammation,
is a pathological hallmark of neurodegenerative diseases including
Parkinson's disease. The
persistent gliosis observed in the Parkinson's
disease substantia nigra (SN) and in humans and animals exposed to
the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) may represent a chronic inflammatory response that
contributes to pathology. We have previously shown that in the
absence of interleukin-6 (IL-6) dopaminergic neurons are more
vulnerable to MPTP. Since IL-6 is both an autocrine and paracrine
proliferation factor for CNS glia, we investigated reactive gliosis
in MPTP-lesioned IL-6 (-/-) mice. While astrogliosis was similar in
injured IL-6 (+/+) and IL-6 (-/-) SN pars compacta (pc),
microgliosis was severely compromised in IL-6 (-/-) mice. In the
absence of IL-6, an acute reactive microgliosis was transient with a
complete absence of reactive Microglia
at day 7 post-lesion. Extensive reactive microgliosis was observed
in the SNpc of MPTP-lesioned IL-6 (+/+) mice. Because glial derived
inducible nitric oxide synthase (iNOS) has been implicated in
dopaminergic cell death, we examined glial iNOS expression in the
IL-6 genotypes to determine if it correlated with the greater
vulnerability and reduced microgliosis observed in the MPTP-lesioned
IL-6 (-/-) nigrostriatal system. Both reactive Microglia
and astrocytes expressed iNOS in the lesioned SNpc. In the IL-6
(-/-) mice, Microglial
iNOS expression diminished as reactive microgliosis declined. The
data suggest IL-6 regulation of Microglia
activation, while iNOS expression appears to be secondary to cell
activation
Choi SH, Joe EH, Kim SU, Jin BK (2003) Thrombin-induced
Microglial
activation produces degeneration of nigral dopaminergic neurons in
vivo. J.Neurosci. 23:5877-5886
Abstract: The present study
examined whether thrombin-induced Microglial
activation could contribute to death of dopaminergic neurons in the
rat substantia nigra (SN) in vivo. Seven days after thrombin
injection into the SN, tyrosine hydroxylase immunohistochemistry
showed a significant loss of nigral dopaminergic neurons. In
parallel, thrombin-activated Microglia,
visualized by immunohistochemical staining using antibodies against
the complement receptor type 3 (OX-42) and the major
histocompatibility complex class II antigens were also observed in
the SN, where degeneration of nigral neurons was found. Reverse
transcription PCR at various time points demonstrated that activated
Microglia
in vivo exhibited an early and transient expression of inducible
nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and several
proinflammatory cytokines, including interleukin 1beta (IL-1beta),
IL-6, and tumor necrosis factor alpha. Western blot analysis and
double-label immunohistochemistry showed an increase in the
expression of iNOS and COX-2 and the colocalization of these
proteins within Microglia.
The thrombin-induced loss of SN dopaminergic neurons was partially
inhibited by NG-nitro-L-arginine methyl ester hydrochloride, an NOS
inhibitor, and by DuP-697, a COX-2 inhibitor. Additional studies
demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2)
and p38 mitogen-activated protein kinase (MAPK) were activated in
the SN as early as 30 min after thrombin injection, and that these
kinases were localized within Microglia.
Inhibition of ERK1/2 and p38 MAPK reduced iNOS and COX-2 mRNA
expression and rescued dopaminergic neurons in the SN. The present
results strongly suggest that Microglial
activation triggered by endogenous compound(s) such as thrombin may
be involved in the neuropathological processes of dopaminergic
neuronal cell death that occur in Parkinson's
disease
Collier TJ, Steece-Collier K, McGuire S, Sortwell CE (2003)
Cellular models to study dopaminergic injury responses.
Ann.N.Y.Acad.Sci. 991:140-151
Abstract: The study of immature
midbrain dopamine (DA) neurons and dopaminergic cell lines in
culture provides an opportunity to analyze mechanisms of cell death
and avenues of potential intervention relevant to Parkinson's
disease (PD) in a controlled environment. Use of cell culture models
has provided evidence for different sets of intracellular changes
associated with DA neuron death following exposure to the
neurotoxins 6-hydroxydopamine and MPP+, supporting roles for
oxidative stress and impaired energy metabolism as significant
factors endangering these cells. Interference with death of cultured
DA neurons has provided an initial test system that has yielded all
the identified neurotrophic factors for DA neurons. More recent work
suggests that combinations of molecules secreted by myelinating
glial cells and their precursors provide even greater
neuroprotection for DA neurons. Most recently, culture systems have
been used to implicate Microglial
activation in DA neuron injury, providing impetus to the
investigation of antiinflammatory agents as potential therapeutics
for PD. Thus, cell culture models provide an important bidirectional
link between mechanistic studies and clinically relevant
observations
Gao HM, Liu B, Hong JS (2003) Critical role for Microglial
NADPH oxidase in rotenone-induced degeneration of dopaminergic
neurons. J.Neurosci. 23:6181-6187
Abstract: Increasing evidence
has suggested an important role for environmental toxins such as
pesticides in the pathogenesis of Parkinson's
disease (PD). Chronic exposure to rotenone, a common herbicide,
reproduces features of Parkinsonism
in rats. Mechanistically, rotenone-induced dopaminergic
neurodegeneration has been associated with both its inhibition of
neuronal mitochondrial complex I and the enhancement of activated
Microglia.
Our previous studies with NADPH oxidase inhibitors, diphenylene
iodonium and apocynin, suggested that NADPH oxidase-derived
superoxide might be a major factor in mediating the
Microglia-enhanced
rotenone neurotoxicity. However, because of the relatively low
specificity of these inhibitors, the exact source of superoxide
induced by rotenone remains to be further determined. In this study,
using primary mesencephalic cultures from NADPH oxidase--null
(gp91phox-/-) or wild-type (gp91phox+/+) mice, we demonstrated a
critical role for Microglial
NADPH oxidase in mediating Microglia-enhanced
rotenone neurotoxicity. In neuron--glia cultures, dopaminergic
neurons from gp91phox-/- mice were more resistant to rotenone
neurotoxicity than those from gp91phox+/+ mice. However, in
neuron-enriched cultures, the neurotoxicity of rotenone was not
different between the two types of mice. More importantly, the
addition of Microglia
prepared from gp91phox+/+ mice but not from gp91phox-/- mice to
neuron-enriched cultures markedly increased rotenone-induced
degeneration of dopaminergic neurons. Furthermore, apocynin
attenuated rotenone neurotoxicity only in the presence of Microglia
from gp91phox+/+ mice. These results indicated that the greatly
enhanced neurotoxicity of rotenone was attributed to the release of
NADPH oxidase-derived superoxide from activated Microglia.
This study also suggested that Microglial
NADPH oxidase may be a promising target for PD treatment
Gao HM, Hong JS, Zhang W, Liu B (2003) Synergistic
dopaminergic neurotoxicity of the pesticide rotenone and inflammogen
lipopolysaccharide: relevance to the etiology of Parkinson's
disease. J.Neurosci. 23:1228-1236
Abstract: Parkinson's
disease (PD) is characterized by a progressive degeneration of the
nigrostriatal dopaminergic pathway resulting in movement disorders.
Although its etiology remains unknown, PD may be the final outcome
of interactions among multiple factors, including exposure to
environmental toxins and the occurrence of inflammation in the
brain. In this study, using primary mesencephalic cultures, we
observed that nontoxic or minimally toxic concentrations of the
pesticide rotenone (0.5 nm) and the inflammogen lipopolysaccharide
(LPS) (0.5 ng/ml) synergistically induced dopaminergic
neurodegeneration. The synergistic neurotoxicity of rotenone and LPS
was observed when the two agents were applied either simultaneously
or in tandem. Mechanistically, Microglial
NADPH oxidase-mediated generation of reactive oxygen species
appeared to be a key contributor to the synergistic dopaminergic
neurotoxicity. This conclusion was based on the following
observations. First, inhibition of NADPH oxidase or scavenging of
free radicals afforded significant neuroprotection. Second, rotenone
and LPS synergistically stimulated the NADPH oxidase-mediated
release of the superoxide free radical. Third and most importantly,
rotenone and LPS failed to induce the synergistic neurotoxicity as
well as the production of superoxide in cultures from NADPH
oxidase-deficient animals. This is the first demonstration that low
concentrations of a pesticide and an inflammogen work in synergy to
induce a selective degeneration of dopaminergic neurons. Findings
from this study may be highly relevant to the elucidation of the
multifactorial etiology of PD and the discovery of effective
therapeutic agents for the treatment of the disease
Gao HM, Liu B, Zhang W, Hong JS (2003) Synergistic
dopaminergic neurotoxicity of MPTP and inflammogen
lipopolysaccharide: relevance to the etiology of Parkinson's
disease. FASEB J. 17:1957-1959
Abstract: Parkinson's
disease (PD) is a profound movement disorder resulting from
progressive degeneration of the nigrostriatal dopaminergic pathway.
Although its etiology remains unknown, increasing evidence suggests
the involvement of multiple factors such as environmental toxins and
genetic susceptibilities in the pathogenesis of PD. In this study
using mesencephalic neuron-glia cultures as an in vitro PD model, we
demonstrated that the neurotoxin
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.1-0.5 microM)
and an inflammogen lipopolysaccharide (LPS, 0.5 ng/ml)
synergistically induced a progressive and selective degeneration of
dopaminergic neurons. The synergistic neurotoxicity was observed
when both agents were applied either simultaneously or in tandem.
The synergistic neurotoxicity was more prominent when lower doses of
both agents were applied for a longer period of time.
Mechanistically, Microglial
NADPH oxidase-mediated generation of reactive oxygen species played
a pivotal role in the synergistic neurotoxicity: MPTP and LPS
synergistically stimulated the NADPH oxidase-mediated release of
superoxide free radical; pharmacological inhibition and genetic
inactivation of NADPH oxidase prevented superoxide production and
the synergistic neurotoxicity. Additionally, inhibition of nitric
oxide synthase afforded significant neuroprotection, suggesting the
involvement of nitric oxide in the synergistic neurotoxicity. This
study lends strong support for a multifactorial etiology of PD and
provides clues for therapeutic interventions
Gao HM, Liu B, Zhang W, Hong JS (2003) Novel
anti-inflammatory therapy for Parkinson's
disease. Trends Pharmacol.Sci. 24:395-401
Abstract: Parkinson's
disease (PD) is a movement disorder that is characterized by
progressive degeneration of the nigrostriatal dopamine system.
Although dopamine replacement can alleviate symptoms of the
disorder, there is no proven therapy to halt the underlying
progressive degeneration of dopamine-containing neurons. Recently,
increasing evidence from human and animal studies has suggested that
neuroinflammation is an important contributor to the neuronal loss
in PD. Moreover, the pro-inflammatory agent lipopolysaccharide
itself can directly initiate degeneration of dopamine-containing
neurons or combine with other environmental factor(s), such as the
pesticide rotenone, to exacerbate such neurodegeneration. These
effects provide strong support for the involvement of inflammation
in the pathogenesis of PD. Furthermore, growing experimental
evidence demonstrates that inhibition of the inflammatory response
can, in part, prevent degeneration of nigrostriatal
dopamine-containing neurons in several animal models of PD,
suggesting that inhibition of inflammation might become a promising
therapeutic intervention for PD
Gao HM, Liu B, Zhang W, Hong JS (2003) Critical role of
Microglial
NADPH oxidase-derived free radicals in the in vitro MPTP model of
Parkinson's disease. FASEB
J. 17:1954-1956
Abstract:
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages
dopaminergic neurons as seen in Parkinson's
disease. Although increasing evidence suggests an involvement of
glia in MPTP neurotoxicity, the nature of this involvement remains
unclear. Exploiting the advantage of cell culture systems, we
demonstrated that Microglia,
but not astroglia, significantly enhanced the progression of
MPTP-induced dopaminergic neurodegeneration. Characterization of the
temporal relationship between neurodegeneration and Microglial
activation demonstrates that reactive microgliosis resulting from
MPTP-initiated neuronal injury, but not direct activation, underlies
the Microglia-enhanced
MPTP neurotoxicity. Mechanistically, through the release of NADPH
oxidase-derived reactive oxygen species, Microglia
contribute to the progressive neuronal damage. Among the factors
measured, the production of extracellular superoxide was the most
prominent. NADPH oxidase inhibitor, apocynin, attenuated
MPTP-induced dopaminergic neurodegeneration only in the presence of
glia. More importantly, dopaminergic neurons from mice lacking NADPH
oxidase, a key enzyme for superoxide production in immune cells, are
significantly more resistant to MPTP neurotoxicity than those from
wild-type controls, and Microglia
dictate the resistance. This study demonstrates that reactive
microgliosis triggered by MPTP-induced neuronal injury and NADPH
oxidase-mediated superoxide production in Microglia
constitute an integral component of MPTP neurotoxicity. This study
also suggests that NADPH oxidase may be a promising target for
therapeutic interventions in Parkinson's
disease
Henningson CT, Jr., Stanislaus MA, Gewirtz AM (2003) 28.
Embryonic and adult stem cell therapy. J.Allergy Clin.Immunol.
111:S745-S753
Abstract: Stem cells are characterized by the
ability to remain undifferentiated and to self-renew. Embryonic stem
cells derived from blastocysts are pluripotent (able to
differentiate into many cell types). Adult stem cells, which were
traditionally thought to be monopotent multipotent, or tissue
restricted, have recently also been shown to have pluripotent
properties. Adult bone marrow stem cells have been shown to be
capable of differentiating into skeletal muscle, brain Microglia
and astroglia, and hepatocytes. Stem cell lines derived from both
embryonic stem and embryonic germ cells (from the embryonic gonadal
ridge) are pluripotent and capable of self-renewal for long periods.
Therefore embryonic stem and germ cells have been widely
investigated for their potential to cure diseases by repairing or
replacing damaged cells and tissues. Studies in animal models have
shown that transplantation of fetal, embryonic stem, or embryonic
germ cells may be able to treat some chronic diseases. In this
review, we highlight recent developments in the use of stem cells as
therapeutic agents for three such diseases: Diabetes, Parkinson
disease, and congestive heart failure. We also discuss the potential
use of stem cells as gene therapy delivery cells and the scientific
and ethical issues that arise with the use of human stem cells
Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A,
Michel PP (2003) The role of glial reaction and inflammation in
Parkinson's disease.
Ann.N.Y.Acad.Sci. 991:214-228
Abstract: The glial reaction is
generally considered to be a consequence of neuronal death in
neurodegenerative diseases such as Alzheimer's disease, Huntington's
disease, and Parkinson's
disease. In Parkinson's
disease, postmortem examination reveals a loss of dopaminergic
neurons in the substantia nigra associated with a massive
astrogliosis and the presence of activated Microglial
cells. Recent evidence suggests that the disease may progress even
when the initial cause of neuronal degeneration has disappeared,
suggesting that toxic substances released by the glial cells may be
involved in the propagation and perpetuation of neuronal
degeneration. Glial cells can release deleterious compounds such as
proinflammatory cytokines (TNF-alpha, Il-1beta, IFN-gamma), which
may act by stimulating nitric oxide production in glial cells, or
which may exert a more direct deleterious effect on dopaminergic
neurons by activating receptors that contain intracytoplasmic death
domains involved in apoptosis. In line with this possibility, an
activation of proteases such as caspase-3 and caspase-8, which are
known effectors of apoptosis, has been reported in Parkinson's
disease. Yet, caspase inhibitors or invalidation of TNF-alpha
receptors does not protect dopaminergic neurons against degeneration
in experimental models of the disease, suggesting that manipulation
of a single signaling pathway may not be sufficient to protect
dopaminergic neurons. In contrast, the antiinflammatory drugs
pioglitazone, a PPAR-gamma agonist, and the tetracycline derivative
minocycline have been shown to reduce glial activation and protect
the substantia nigra in an animal model of the disease. Inhibition
of the glial reaction and the inflammatory processes may thus
represent a therapeutic target to reduce neuronal degeneration in
Parkinson's disease
Liu B, Gao HM, Hong JS (2003) Parkinson's
disease and exposure to infectious agents and pesticides and the
occurrence of brain injuries: role of neuroinflammation.
Environ.Health Perspect. 111:1065-1073
Abstract: Idiopathic
Parkinson's disease (PD) is
a devastating movement disorder characterized by selective
degeneration of the nigrostriatal dopaminergic pathway.
Neurodegeneration usually starts in the fifth decade of life and
progresses over 5-10 years before reaching the fully symptomatic
disease state. Despite decades of intense research, the etiology of
sporadic PD and the mechanism underlying the selective neuronal loss
remain unknown. However, the late onset and slow-progressing nature
of the disease has prompted the consideration of environmental
exposure to agrochemicals, including pesticides, as a risk factor.
Moreover, increasing evidence suggests that early-life occurrence of
inflammation in the brain, as a consequence of either brain injury
or exposure to infectious agents, may play a role in the
pathogenesis of PD. Most important, there may be a self-propelling
cycle of inflammatory process involving brain immune cells
(Microglia
and astrocytes) that drives the slow yet progressive
neurodegenerative process. Deciphering the molecular and cellular
mechanisms governing those intricate interactions would
significantly advance our understanding of the etiology and
pathogenesis of PD and aid the development of therapeutic strategies
for the treatment of the disease
Liu B, Hong JS (2003) Role of Microglia
in inflammation-mediated neurodegenerative diseases: mechanisms and
strategies for therapeutic intervention. J.Pharmacol.Exp.Ther.
304:1-7
Abstract: Evidence from postmortem analysis implicates
the involvement of Microglia
in the neurodegenerative process of several degenerative
neurological diseases, including Alzheimer's disease and Parkinson's
disease. It remains to be determined, however, whether Microglial
activation plays a role in the initiation stage of disease
progression or occurs merely as a response to neuronal death.
Activated Microglia
secrete a variety of proinflammatory and neurotoxic factors that are
believed to induce and/or exacerbate neurodegeneration. In this
article, we summarize recent advances on the study of the role of
Microglia
based on findings from animal and cell culture models in the
pathogenesis of neurodegenerative diseases, with particular emphasis
on Parkinson's disease. In
addition, we also discuss novel approaches to potential therapeutic
strategies
Muramatsu Y, Kurosaki R, Watanabe H, Michimata M, Matsubara
M, Imai Y, Araki T (2003) Expression of S-100 protein is related to
neuronal damage in MPTP-treated mice. Glia 42:307-313
Abstract:
S-100beta is a calcium-binding protein expressed at high levels in
brain and is known as a marker of brain damage. However, little is
known about the role of S-100beta protein during neuronal damage
caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To
determine whether S-100beta protein is induced in glial cells after
MPTP treatment, we investigated the expression of S-100 protein
immunohistochemically, using MPTP-treated mice. We also examined the
change of neurons and glial cells in mice after MPTP treatment. The
present study shows that tyrosine hydroxylase (TH) immunoreactivity
decreased gradually in the striatum and substantia nigra from 1 day
after MPTP treatment. Thereafter, TH-immunopositive cells and fibers
decreased in the striatum and substantia nigra at 3 days after MPTP
treatment. In contrast, S-100-immunopositive cells and glial
fibrillary acidic protein (GFAP)-immunopositive cells increased
markedly in the striatum and substantia nigra at 3 days after MPTP
treatment. Seven days after MPTP treatment, S-100-immunopositive
cells decreased in the striatum and substantia nigra. However, the
number of GFAP-immunopositive cells increased in these regions. In
double-labeled immunostaining with anti-S-100 and anti-GFAP
antibodies, S-100 immunoreactivity was observed only in the
GFAP-positive astrocytes. These results provide evidence that
astrocytic activation may play a role in the pathogenesis of
MPTP-induced degeneration of dopaminergic neurons. Furthermore, the
present study demonstrates that S-100 protein is expressed
selectively by astrocytes, but not by Microglia,
after MPTP treatment. These results provide valuable information for
the pathogenesis of the acute stage of Parkinson's
disease
Piao YS, Mori F, Hayashi S, Tanji K, Yoshimoto M, Kakita A,
Wakabayashi K, Takahashi H (2003) Alpha-synuclein pathology
affecting Bergmann glia of the cerebellum in patients with
alpha-synucleinopathies. Acta Neuropathol.(Berl)
105:403-409
Abstract: We carried out immunohistochemical
examinations of the brains (cerebella) of patients who had suffered
from Parkinson's disease
(PD), diffuse Lewy body disease (DLBD) or multiple system atrophy
(MSA), using antibodies specific for alpha-synuclein.
Alpha-synuclein-positive doughnut-shaped structures were found
occasionally in the cerebellar molecular layer in some of these
patients. Double-labeling immunofluorescence and immunoelectron
microscopy studies revealed that these alpha-synuclein-positive
doughnut-shaped structures were located in the glial fibrillary
acidic protein-positive radial processes of Bergmann glia,
corresponding to the outer area of Lewy body-like inclusions, and
consisted of granulo-filamentous structures. These findings indicate
that, although not frequently, Bergmann glia of the cerebellum are
also the targets of alpha-synuclein pathology in
alpha-synucleinopathies such as PD, DLBD and MSA
Riess O, Berg D, Kruger R, Schulz JB (2003) Therapeutic
strategies for Parkinson's
disease based on data derived from genetic research. J.Neurol. 250
Suppl 1:I3-10
Abstract: Following the identification of mutations
in alpha-synuclein as the cause of some rare forms of familial
Parkinson's disease (PD),
genetic research has uncovered numerous gene loci of PD. Meanwhile,
several neurodegenerative diseases have been shown to accumulate
a-synuclein in neuronal and glial cells summarizing this group of
diseases as synucleinopathies. All currently known gene defects
causing PD alter the ubiquitin-proteasomal pathway of protein
degradation. Identification of these disease mutations allows
studying the functional consequences which lead to cellular
dysfunction and cell death in cell culture and transgenic animal
models, to identify therapeutic targets and to test potential
protective strategies in these models
Saura J, Pares M, Bove J, Pezzi S, Alberch J, Marin C, Tolosa
E, Marti MJ (2003) Intranigral infusion of interleukin-1beta
activates astrocytes and protects from subsequent 6-hydroxydopamine
neurotoxicity. J.Neurochem. 85:651-661
Abstract: Activation of
glial cells is a prevalent response to neuronal damage in brain
disease and ageing, with potential neuroprotective and neurotoxic
consequences. We were interested in studying the role of glial
activation on dopaminergic neurons of the substantia nigra in an
animal model of Parkinson's
disease. Thus, we evaluated the effect of a pre-existing glial
activation on the dopaminergic neuronal death induced by striatal
infusion of 6-hydroxydopamine. We established a model of local glial
activation by stereotaxic infusion of interleukin-1beta in the
substantia nigra of adult rats. Interleukin-1beta (20 ng) induced a
marked activation of astrocytes at days 2, 5 and 10, revealed by
heat-shock protein 27 and glial fibrillary acid protein
immunohistochemistry, but did not affect the Microglial
markers OX-42 and heat-shock proteins 32 or 47. Intranigral infusion
of interleukin-1beta 5 days before a striatal injection of
6-hydroxydopamine significantly protected nigral dopaminergic cell
bodies, but not striatal terminals from the 6-hydroxydopamine
lesion. Also, in the animals pre-treated with interleukin-1beta, a
significant prevention of 6-hydroxydopamine-induced reduction of
adjusting steps, but not of 6-hydroxydopamine-induced amphetamine
rotations, were observed. These data show the characterization of a
novel model of local astroglial activation in the substantia nigra
and support the hypothesis of a neuroprotective role of activated
astrocytes in Parkinson's
disease
Sherer TB, Betarbet R, Kim JH, Greenamyre JT (2003) Selective
Microglial
activation in the rat rotenone model of Parkinson's
disease. Neurosci.Lett. 341:87-90
Abstract: Chronic rotenone
exposure reproduces features of Parkinson's
disease (PD) (Nat. Neurosci. 3 (2000) 1301; Exp. Neurol. 179 (2003)
9). We investigated the role of glial activation in rotenone
toxicity in vivo. Male Lewis rats received 2-3 mg/kg rotenone per
day for up to 4 weeks. In 50% of surviving rotenone-treated animals,
there was nigrostriatal dopaminergic degeneration, marked by reduced
tyrosine hydroxylase immunoreactivity). Extensive Microglial
activation, determined by OX-42-ir, occurred in striatum and nigra
of rotenone-treated animals, and was prominent before anatomical
evidence of dopaminergic lesions. Microglia
enlarged and developed short, stubby processes in rotenone-treated
animals. Rotenone-induced Microglial
activation was less pronounced in cortex. Reactive astrocytosis was
minimal and limited to a thin rim around the lesion. Marked
Microglial
activation with minimal astrocytosis is another pathological feature
of PD reproduced by rotenone treatment
Sugama S, Yang L, Cho BP, DeGiorgio LA, Lorenzl S, Albers DS,
Beal MF, Volpe BT, Joh TH (2003) Age-related Microglial
activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice. Brain
Res. 964:288-294
Abstract: Microglial
activation was investigated in the brains of young (3 months old)
and older (9-12 months old) mice following administration of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tyrosine
hydroxylase (TH)-positive neuronal loss differed significantly
between young and older mice. Importantly, the two groups clearly
demonstrated a distinct Microglial
activation pattern. In young mice which showed TH neuronal loss at 1
day (33.4%), 3 days (45.1%), 7 days (47.1%) and 14 days (46.9%),
Microglial
activation was first observed at 1 day, with lesser activation at 3
days and none shown later than 7 days. In contrast, in older mice
which showed TH neuronal loss at 1 day (49.6%), 3 days (56.1%), 7
days (71.7%) and 14 days (72.1%), Microglial
activation occurred at 1 day, further intensified at 3-7 days, and
was largely abated by 14 days. The double immunohistochemistry
further demonstrated that the activated Microglia
surrounded dopaminergic neurons in older mice at 7 days, which was
sharply in contrast to the young mice which were devoid of massive
Microglial
activation in the SN later than 3 days after MPTP treatment. The
present study suggests that age-related Microglial
activation in the SN may be relevant to the higher susceptibility to
MPTP neurotoxicity in older mice
Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M,
Jackson-Lewis V, Przedborski S (2003) Cyclooxygenase-2 is
instrumental in Parkinson's
disease neurodegeneration. Proc.Natl.Acad.Sci.U.S.A
100:5473-5478
Abstract: Parkinson's
disease (PD) is a neurodegenerative disorder of uncertain
pathogenesis characterized by the loss of the nigrostriatal
dopaminergic neurons, which can be modeled by the neurotoxin
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Increased
expression of cyclooxygenase type 2 (COX-2) and production of
prostaglandin E(2) have been implicated in neurodegeneration in
several pathological settings. Here we show that COX-2, the
rate-limiting enzyme in prostaglandin E(2) synthesis, is
up-regulated in brain dopaminergic neurons of both PD and MPTP mice.
COX-2 induction occurs through a JNKc-Jun-dependent mechanism after
MPTP administration. We demonstrate that targeting COX-2 does not
protect against MPTP-induced dopaminergic neurodegeneration by
mitigating inflammation. Instead, we provide evidence that COX-2
inhibition prevents the formation of the oxidant species
dopamine-quinone, which has been implicated in the pathogenesis of
PD. This study supports a critical role for COX-2 in both the
pathogenesis and selectivity of the PD neurodegenerative process.
Because of the safety record of the COX-2 inhibitors, and their
ability to penetrate the blood-brain barrier, these drugs may be
therapies for PD
Teismann P, Tieu K, Cohen O, Choi DK, Wu dC, Marks D, Vila M,
Jackson-Lewis V, Przedborski S (2003) Pathogenic role of glial cells
in Parkinson's disease. Mov
Disord. 18:121-129
Abstract: Parkinson's
disease (PD) is a common neurodegenerative disorder characterized by
the progressive loss of the dopaminergic neurons in the substantia
nigra pars compacta (SNpc). The loss of these neurons is associated
with a glial response composed mainly of activated Microglial
cells and, to a lesser extent, of reactive astrocytes. This glial
response may be the source of trophic factors and can protect
against reactive oxygen species and glutamate. Alternatively, this
glial response can also mediate a variety of deleterious events
related to the production of pro-oxidant reactive species, and
pro-inflammatory prostaglandin and cytokines. We discuss the
potential protective and deleterious effects of glial cells in the
SNpc of PD and examine how those factors may contribute to the
pathogenesis of this disease
Wilms H, Rosenstiel P, Sievers J, Deuschl G, Zecca L, Lucius
R (2003) Activation of Microglia
by human neuromelanin is NF-kappaB dependent and involves p38
mitogen-activated protein kinase: implications for Parkinson's
disease. FASEB J. 17:500-502
Abstract: It has been suggested that
Microglial
inflammation augments the progression of Parkinson's
disease (PD). However, endogenous factors initiating Microglial
activation are largely unknown. We therefore investigated the
effects of human neuromelanin (NM) on the release of neurotoxic
mediators and the underlying signaling pathways from rat Microglia
in vitro. The addition of NM to Microglial
cultures induced positive chemotactic effects, activated the
proinflammatory transcription factor nuclear factor kappaB
(NF-kappaB) via phosphorylation and degradation of the inhibitor
protein kappaB (IkappaB), and led to an up-regulation of tumor
necrosis factor alpha, interleukin-6, and nitric oxide. The
impairment of NF-kappaB function by the IkappaB kinase inhibitor
sulfasalazine was paralleled by a decline in neurotoxic mediators.
NM also activated p38 mitogen-activated protein kinase (MAPK), the
inhibition of this pathway by SB203580 diminished phosphorylation of
the transactivation domain of the p65 subunit of NF-kappaB. These
findings demonstrate a crucial role of NM in the pathogenesis of PD
by augmentation of Microglial
activation, leading to a vicious cycle of neuronal death, exposure
of additional neuromelanin, and chronification of inflammation. The
antagonization of Microglial
activation by a pharmacological intervention targeting Microglial
NF-kappaB or p38 MAPK could point to additional venues in the
treatment of PD
Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V,
Ischiropoulos H, Przedborski S (2003) NADPH oxidase mediates
oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
model of Parkinson's
disease. Proc.Natl.Acad.Sci.U.S.A 100:6145-6150
Abstract:
Parkinson's disease (PD) is
a neurodegenerative disorder of uncertain pathogenesis characterized
by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA)
neurons, and can be modeled by the neurotoxin
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both
inflammatory processes and oxidative stress may contribute to
Wullner U, Klockgether T (2003) Inflammation in Parkinson's
disease. J.Neurol. 250 Suppl 1:I35-I38
Abstract: Several studies
of Parkinson's disease (PD)
patients and experimental models of PD indicate the presence of an
inflammatory process in PD. Although the primary cellular mechanisms
remain to be clarified, activation of resident Microglia
appears to aggravate or even maintain the disease process in PD.
Modulation of inflammatory mechanisms could provide a new
neuroprotective therapy in PD
Al Sarraj S, Maekawa S, Kibble M, Everall I, Leigh N (2002)
Ubiquitin-only intraneuronal inclusion in the substantia nigra is a
characteristic feature of motor neurone disease with dementia.
Neuropathol.Appl.Neurobiol. 28:120-128
Abstract: Two types of
ubiquitinated inclusions have been described in motor neurone
disease (MND). (1) Skein or globular ubiquitinated inclusions in the
motor neurones (more frequently in the lower motor neurones). This
is a characteristic feature of all motor neurone disease categories.
(2) Dot-shape or crescentric ubiquitinated inclusions in the upper
layers of cortex and dentate gyrus described in cases of motor
neurone disease with dementia (DMND). We investigated the substantia
nigra (SN) in MND cases; two cases of motor neurone disease
inclusion body (MND-IB) dementia, six cases of DMND, 14 cases of MND
(including one case from Guam and two cases of familial SOD1
mutation), four cases of Parkinson's
disease (PD), and 10 cases of age-matched normal controls. SN and
spinal cord sections were stained with ubiquitin (alpha-synuclein,
tau, PGM1, SMI-31 and SOD1 antibodies). The neuronal density in SN
was quantified by using a computer-based image analysis system. Four
out of six DMND cases showed rounded ubiquitin positive inclusions
with irregular frayed edges, associated with neuronal loss, reactive
astrocytosis and a large number of activated Microglia
cells. These inclusions are negative with antibodies to
(alpha-synuclein, tau, SMI-31 and SOD1). The SN in cases from MND-IB
dementia and MND showed occasional neuronal loss and no inclusions.
The ubiquitin-only inclusions in SN of DMND cases are similar (but
not identical) to the ubiquitinated inclusions described previously
in the spinal cord of MND cases and are distinct from Lewy bodies
(LBs). The degeneration of SN is most likely a primary
neurodegenerative process of motor neurone disease type frequently
involving the DMND cases. MND disease is a spectrum and multisystem
disorder with DMND located at the extreme end of a spectrum
affecting the CNS more widely than just the motor system
Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM,
Hirsch EC (2002) Protective action of the peroxisome
proliferator-activated receptor-gamma agonist pioglitazone in a
mouse model of Parkinson's
disease. J.Neurochem. 82:615-624
Abstract: We examined the effect
of pioglitazone, a peroxisome proliferator-activated receptor-gamma
(PPARgamma) agonist of the thiazolidinedione class, on dopaminergic
nerve cell death and glial activation in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of
Parkinson's disease. The
acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal
injury, as determined by tyrosine hydroxylase (TH)
immunocytochemistry, and HPLC detection of striatal dopamine and
metabolites. Damage to the nigrostriatal dopamine system was
accompanied by a transient activation of Microglia,
as determined by macrophage antigen-1 (Mac-1) and inducible nitric
oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic
response. Orally administered pioglitazone (approximately 20
mg/kg/day) attenuated the MPTP-induced glial activation and
prevented the dopaminergic cell loss in the substantia nigra pars
compacta (SNpc). In contrast, there was little reduction of
MPTP-induced dopamine depletion, with no detectable effect on loss
of TH immunoreactivity and glial response in the striatum of
pioglitazone-treated animals. Low levels of PPARgamma expression
were detected in the ventral mesencephalon and striatum, and were
unaffected by MPTP or pioglitazone treatment. Since pioglitazone
affects primarily the SNpc in our model, different
PPARgamma-independent mechanisms may regulate glial activation in
the dopaminergic terminals compared with the dopaminergic cell
bodies after acute MPTP intoxication
Castano A, Herrera AJ, Cano J, Machado A (2002) The
degenerative effect of a single intranigral injection of LPS on the
dopaminergic system is prevented by dexamethasone, and not mimicked
by rh-TNF-alpha, IL-1beta and IFN-gamma. J.Neurochem.
81:150-157
Abstract: It is becoming widely accepted that the
inflammatory response is involved in neurodegenerative disease. In
this context, we have developed an animal model of dopaminergic
system degeneration by the intranigral injection of
lipopolysaccharide (LPS), a potent inductor of inflammation. To
address the importance of the inflammatory response in the
LPS-induced degeneration of nigral dopaminergic neurones, we carried
out two different kinds of studies: (i) the possible protective
effect of an anti-inflammatory compound, and (ii) the effect of the
intranigral injection of inflammatory cytokines (TNF-alpha, IL-1beta
and IFN-gamma) on dopaminergic neurones viability. Present results
show that dexamethasone, a potent anti-inflammatory drug that
interferes with many of the features characterizing pro-inflammatory
glial activation, prevented the loss of catecholamine content,
Tyrosine hydroxylase (TH) activity and TH immunostaining induced by
LPS-injection and also the bulk activation of Microglia/macrophages.
Surprisingly, injection of the pro-inflammatory cytokines failed to
reproduce the LPS effect. Taken together, our results suggest that
inflammatory response is implicated in LPS-induced
neurodegeneration. This damage may be due, at least in part, to a
cascade of events independent of that described for TNF-alpha/IL-1
beta/IFN-gamma
Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E,
Isacson O (2002) Neuroinflammation of the nigrostriatal pathway
during progressive 6-OHDA dopamine degeneration in rats monitored by
immunohistochemistry and PET imaging. Eur.J.Neurosci.
15:991-998
Abstract: We investigated the Microglial
response to progressive dopamine neuron degeneration using in vivo
positron emission tomography (PET) imaging and postmortem analyses
in a Parkinson's disease
(PD) rat model induced by unilateral (right side) intrastriatal
administration of 6-hydroxydopamine (6-OHDA). Degeneration of the
dopamine system was monitored by PET imaging of presynaptic dopamine
transporters using a specific ligand (11)C-CFT
(2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane). Binding of
(11)C-CFT was markedly reduced in the striatum indicating
dopaminergic degeneration. Parallel PET studies of (11)C-PK11195
(1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3 isoquinoline
carboxamide) (specific ligand for activated Microglia)
showed increased binding in the striatum and substantia nigra
indicative of a Microglial
response. Postmortem immunohistochemical analyses were performed
with antibodies against CR3 for Microglia/macrophage
activation. Using a qualitative postmortem index for Microglial
activation we found an initially focal, then widespread Microglial
response at striatal and nigral levels at 4 weeks postlesion. These
data support the hypothesis that inflammation is a significant
component of progressive dopaminergic degeneration that can be
monitored by PET imaging
Czlonkowska A, Kurkowska-Jastrzebska I, Czlonkowski A, Peter
D, Stefano GB (2002) Immune processes in the pathogenesis of
Parkinson's disease - a
potential role for Microglia
and nitric oxide. Med.Sci.Monit. 8:RA165-RA177
Abstract: It has
been known for many years that immune system alterations occur in
Parkinson's disease (PD).
Changes in lymphocyte populations in cerebrospinal fluid and blood,
immunoglobulin synthesis, and cytokine and acute phase protein
production have been observed in patients with PD. In this regard,
PD patients exhibit a lower frequency of infections and cancer,
suggesting that immune system stimulation may occur. This hypothesis
is further supported by the observation of T-cell activation leading
to the production of interferon gamma in PD. As in other CNS
degenerative diseases, in damaged regions in the brains of PD
patients, there is evidence of inflammation, characterized by glial
reaction (especially Microglia),
as well as increased expression of HLA-DR antigens, cytokines, and
components of complement. These observations suggest that immune
system mechanisms are involved in the pathogenesis of neuronal
damage in PD. The cellular mechanisms of primary injury in PD have
not been clarified, however, but it is likely that mitochondrial
mutations, oxidative stress and apoptosis play a role. Furthermore,
inflammation initiated by neuronal damage in the striatum and the
substantia nigra in PD may aggravate the course of the disease.
These observations suggest that treatment with anti-inflammatory
drugs may act to slow progression of PD
Gao HM, Hong JS, Zhang W, Liu B (2002) Distinct role for
Microglia
in rotenone-induced degeneration of dopaminergic neurons.
J.Neurosci. 22:782-790
Abstract: Increasing evidence has
suggested an important role for environmental factors such as
exposure to pesticides in the pathogenesis of Parkinson's
disease. In experimental animals the exposure to a common herbicide,
rotenone, induces features of Parkinsonism;
mechanistically, rotenone-induced destruction of dopaminergic
neurons has been attributed to its inhibition of the activity of
neuronal mitochondrial complex I. However, the role of Microglia,
the resident brain immune cells in rotenone-induced
neurodegeneration, has not been reported. Using primary
neuron-enriched and neuron/glia cultures from the rat mesencephalon,
we discovered an extraordinary feature for rotenone-induced
degeneration of cultured dopaminergic neurons. Although little
neurotoxicity was detected in neuron-enriched cultures after
treatment for 8 d with up to 20 nm rotenone, significant and
selective dopaminergic neurodegeneration was observed in neuron/glia
cultures 2 d after treatment with 20 nm rotenone or 8 d after
treatment with 1 nm rotenone. The greatly enhanced neurodegenerative
ability of rotenone was attributed to the presence of glia,
especially Microglia,
because the addition of Microglia
to neuron-enriched cultures markedly increased their susceptibility
to rotenone. Mechanistically, rotenone stimulated the release of
superoxide from Microglia
that was attenuated by inhibitors of NADPH oxidase. Furthermore,
inhibition of NADPH oxidase or scavenging of superoxide
significantly reduced the rotenone-induced neurotoxicity. This is
the first report demonstrating that Microglia
play a pivotal role in rotenone-induced degeneration of dopaminergic
neurons. The results of this study should advance our understanding
of the mechanism of action for pesticides in the pathogenesis of
Parkinson's disease
Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002)
Microglial
activation-mediated delayed and progressive degeneration of rat
nigral dopaminergic neurons: relevance to Parkinson's
disease. J.Neurochem. 81:1285-1297
Abstract: The etiology of
sporadic Parkinson's
disease (PD) remains unknown. Increasing evidence has suggested a
role for inflammation in the brain in the pathogenesis of PD.
However, it has not been clearly demonstrated whether Microglial
activation, the most integral part of the brain inflammatory
process, will result in a delayed and progressive degeneration of
dopaminergic neurons in substantia nigra, a hallmark of PD. We
report here that chronic infusion of an inflammagen
lipopolysaccharide at 5 ng/h for 2 weeks into rat brain triggered a
rapid activation of Microglia
that reached a plateau in 2 weeks, followed by a delayed and gradual
loss of nigral dopaminergic neurons that began at between 4 and 6
weeks and reached 70% by 10 weeks. Further investigation of the
underlying mechanism of action of Microglia-mediated
neurotoxicity using rat mesencephalic neuron-glia cultures
demonstrated that low concentrations of lipopolysaccharide (0.1-10
ng/mL)-induced Microglial
activation and production of neurotoxic factors preceded the
progressive and selective degeneration of dopaminergic neurons.
Among the factors produced by activated Microglia,
the NADPH oxidase-mediated release of superoxide appeared to be a
predominant effector of neurodegeneration, consistent with the
notion that dopaminergic neurons are particularly vulnerable to
oxidative insults. This is the first report that Microglial
activation induced by chronic exposure to inflammagen was capable of
inducing a delayed and selective degeneration of nigral dopaminergic
neurons and that Microglia-originated
free radicals play a pivotal role in dopaminergic neurotoxicity in
this inflammation-mediated model of PD
He Y, Le WD, Appel SH (2002) Role of Fcgamma receptors in
nigral cell injury induced by Parkinson
disease immunoglobulin injection into mouse substantia nigra.
Exp.Neurol. 176:322-327
Abstract: Immune/inflammatory factors
have been implicated in the pathogenesis of Parkinson's
disease (PD). Immunoglobulin G (IgG) from patients with PD can
induce injury of dopaminergic neurons following stereotaxic
injection into rat substantia nigra (SN). The PD IgG can be
demonstrated in vitro to activate Microglia
via the Fcgamma receptor (Fcgamma R) and induce dopaminergic cell
injury. To confirm the involvement of Microglia
and their Fcgamma R in IgG-induced lesions of SN in vivo we analyzed
the tyrosine hydroxylase (TH)-positive cell loss in SN par compacta
(SNpc) in mice lacking Fcgamma receptors (Fcgamma R(-/-)) and wild
type (Fcgamma R(+/+)). At 1 day after stereotaxic injection of PD
IgG into the SN of Fcgamma R(+/+) mice there was a 27% increase in
the number of CD11b-positive Microglial
cells and no significant loss of TH-positive cells. At 14 days after
the stereotaxic injection, the number of Microglial
cells was increased by 42%, accompanied by a 40% loss of TH-positive
neurons in the SNpc. PD IgG injection in Fcgamma R(-/-) mice
resulted in no significant increase of Microglia
and no loss of TH-positive cells in the SNpc at any time point. The
injection of F(ab')(2) fragments of PD IgG was able to induce
TH-positive neuronal loss in the SNpc only when the injected animals
raised antibodies against the injected human IgG fragments, which
confirmed the importance of the Fcgamma R in Microglial
activation and nigral injury
Iravani MM, Kashefi K, Mander P, Rose S, Jenner P (2002)
Involvement of inducible nitric oxide synthase in
inflammation-induced dopaminergic neurodegeneration. Neuroscience
110:49-58
Abstract: The loss of dopaminergic neurones in the
substantia nigra with Parkinson's
disease may result from inflammation-induced proliferation of
Microglia
and reactive macrophages expressing inducible nitric oxide synthase
(iNOS). We have investigated the effects of the supranigral
administration of lipopolysaccharide on iNOS-immunoreactivity,
3-nitrotyrosine formation and tyrosine hydroxylase-immunoreactive
neuronal number, and retrogradely labelled fluorogold-positive
neurones in the ventral mesencephalon in male Wistar rats. Following
supranigral lipopolysaccharide injection, 16-18 h previously, there
was intense expression of NADPH-diaphorase and iNOS-immunoreactivity
in non-neuronal, macrophage-like cells. This was accompanied by
intense expression of glial fibrillary acidic protein-immunoreactive
astrocytosis in the substantia nigra. There were also significant
reductions in the number of tyrosine hydroxylase(50-60%)- and
fluorogold (65-75%)-positive neurones in the substantia nigra. In
contrast, tyrosine hydroxylase-immunoreactivity in the ventral
tegmental area was not altered. Pre-treatment of animals with the
iNOS inhibitor, S-methylisothiourea (10 mg kg(-1), i.p.), led to a
significant reduction of lipopolysaccharide-induced cell death.
Similar reduction of tyrosine hydroxylase-immunoreactivity and
fluorogold-labelled neurones in the substantia nigra following
lipopolysaccharide administration suggests dopaminergic cell death
rather than down-regulation of tyrosine hydroxylase. We conclude
that the expression of iNOS- and 3-nitrotyrosine-immunoreactivity
and reduction of cell death by S-methylisothiourea suggest the
effects of lipopolysaccharide may be nitric oxide-mediated, although
other actions of lipopolysaccharide (independent of iNOS induction)
cannot be ruled out
Koutsilieri E, Scheller C, Grunblatt E, Nara K, Li J,
Riederer P (2002) Free radicals in Parkinson's
disease. J.Neurol. 249 Suppl 2:II1-II5
Abstract: Although there
are a number of hypotheses to explain the pathobiochemistry of
Parkinson's disease (PD),
the one on oxidative stress (OS) has gained major interest. The
evidence for OS participation as a cause of PD can be summarized as
follows: 1) OS is involved in physiological aging, 2) there is ample
evidence that OS is significantly enhanced in PD compared to
age-matched healthy persons, 3) OS is an early feature of PD because
OS-dependent aggregation of proteins in the form of advanced
glycation end products can be imaged in Lewy bodies at a time in a
person's life, when no phenotype of a neurodegenerative disorder is
evident, 4) Experimental models of PD show OS and degeneration of
dopaminergic neurons. The toxin-induced neurodegeneration can be
blocked by antioxidants, and 5) Activated Microglia,
known to release free radicals and inflammatory cytokines, are
present in brains of Parkinsonian
patients.In conclusion, a great body of evidence points to the view
that OS is a major component underlying the pathobiochemistry of PD.
Together a genetic disposition and endogenous/exogenous toxic events
of various origins result in a synergistic cascade of toxicity which
leads to dysfunction and finally to cell death of dopaminergic
neurons. Again, OS plays a significant role in generating cell death
signals including apoptosis
Koutsilieri E, Scheller C, Tribl F, Riederer P (2002)
Degeneration of neuronal cells due to oxidative stress--Microglial
contribution. Parkinsonism.Relat
Disord. 8:401-406
Abstract: Various neurodegenerative disorders
including Parkinson's
disease, Alzheimer's disease and amyotrophic lateral sclerosis have
been causally linked to the generation of free radicals and
oxidative stress. In this review, we discuss the implication of
oxidative stress in neuronal death and point out the role of
intracellular signaling pathways leading to activation of
transcription factors associated with cell death and repair. In
particular, the impact of Microglia
as contributors in promoting oxidative stress in neurodegeneration
is highlighted. Finally, pivotal molecular targets for drug
therapies of brain disorders are reported
Kramer BC, Yabut JA, Cheong J, JnoBaptiste R, Robakis T,
Olanow CW, Mytilineou C (2002) Lipopolysaccharide prevents cell
death caused by glutathione depletion: possible mechanisms of
protection. Neuroscience 114:361-372
Abstract: Glutathione is an
important cellular antioxidant present at high concentrations in the
brain. We have previously demonstrated that depletion of glutathione
in mesencephalic cultures results in cell death and that the
presence of glia is necessary for the expression of toxicity. Cell
death following glutathione depletion can be prevented by inhibition
of lipoxygenase activity, implicating arachidonic acid metabolism in
the toxic events. In this study we examined the effect of glial
activation, known to cause secretion of cytokines and release of
arachidonic acid, on the toxicity induced by glutathione depletion.
Our data show that treatment with the endotoxin lipopolysaccharide
activated glial cells in mesencephalic cultures, increased
interleukin-1beta in Microglia
and caused depletion of glutathione. The overall effect of
lipopolysaccharide treatment, however, was protection from damage
caused by glutathione depletion. Addition of cytokines or growth
factors, normally secreted by activated glia, did not modify
L-buthionine sulfoximine toxicity, although basic fibroblast growth
factor provided some protection. A large increase in the protein
content and the activity of Mn-superoxide dismutase, observed after
lipopolysaccharide treatment, may indicate a role for this
mitochondrial antioxidant enzyme in the protective effect of
lipopolysaccharide. This was supported by the suppression of
toxicity by exogenous superoxide dismutase. Our data suggest that
superoxide contributes to the damage caused by glutathione depletion
and that up-regulation of superoxide dismutase may offer protection
in neurodegenerative diseases associated with glutathione depletion
and oxidative stress
Kurkowska-Jastrzebska I, Babiuch M, Joniec I, Przybylkowski
A, Czlonkowski A, Czlonkowska A (2002) Indomethacin protects against
neurodegeneration caused by MPTP intoxication in mice.
Int.Immunopharmacol. 2:1213-1218
Abstract: The anti-inflammatory
agents are postulated to be effective in treating neurodegenerative
disorders. In this study, we showed that indomethacin (IND) in the
dose of 1 mg/kg protected neurons against toxic damage caused by
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice model of
Parkinson's disease. IND
also diminished Microglial
activation and lymphocytic infiltration in the injured areas. These
observations suggest that anti-inflammatory properties of IND may
play a role in the neuron's protection in this model. However,
diminished inflammatory reaction may be secondary to less neuronal
damage
Lee YB, Nagai A, Kim SU (2002) Cytokines, chemokines, and
cytokine receptors in human Microglia.
J.Neurosci.Res. 69:94-103
Abstract: Enriched populations of human
Microglial
cells were isolated from mixed cell cultures prepared from embryonic
human telencephalon tissues. Human Microglial
cells exhibited cell type-specific antigens for macrophage-Microglia
lineage cells including CD11b (Mac-1), CD68, B7-2 (CD86), HLA-ABC,
HLA-DR and ricinus communis aggulutinin lectin-1 (RCA-1), and
actively phagocytosed latex beads. Gene expression and protein
production of cytokines, chemokines and cytokine/chemokine receptors
were investigated in the purified populations of human Microglia.
Normal unstimulated human Microglia
expressed constitutively mRNA transcripts for interleukin- 1beta
(IL-1beta) -6, -8, -10, -12, -15, tumor necrosis factor-alpha
(TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha),
MIP-1beta, and monocyte chemoattractant protein-1 (MCP-1), while
treatment with lipopolysaccharide (LPS) or amyloid beta peptides
(Abeta) led to increased expression of mRNA levels of IL-8, IL-10,
IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and MCP-1. Human Microglia,
in addition, expressed mRNA transcripts for IL-1RI, IL-1RII, IL-5R,
IL-6R, IL-8R, IL-9R, IL-10R, IL-12R, IL-13R, and IL-15R.
Enzyme-linked immunosorbent assays (ELISA) showed increased protein
levels in culture media of IL-1beta, IL-8, TNF-alpha, and MIP-1alpha
in human Microglia
following treatment with LPS or Abeta. Increased TNF-alpha release
from human Microglia
following LPS treatment was completely inhibited with IL-10
pretreatment, but not with IL-6, IL-9, IL-12, IL-13, or transforming
growth factor-beta (TGF-beta). Present results should help in
understanding the basic Microglial
biology, but also the pathophysiology of activated Microglia
in neurological diseases such as Alzheimer disease, Parkinson
disease, Huntington disease, amyotrophic lateral sclerosis, stroke,
and neurotrauma
Lorenzl S, Albers DS, Narr S, Chirichigno J, Beal MF (2002)
Expression of MMP-2, MMP-9, and MMP-1 and their endogenous
counterregulators TIMP-1 and TIMP-2 in postmortem brain tissue of
Parkinson's disease.
Exp.Neurol. 178:13-20
Abstract: We investigated the levels and
tissue localization of matrix metalloproteinase 2 (MMP-2) and matrix
metalloproteinase 9 (MMP-9) in postmortem brain tissue from
Parkinson's disease (PD)
and age-matched control cases. Using zymography, we found reduced
MMP-2 levels in PD cases in the substantia nigra as compared to
controls; levels of MMP-2 were not significantly changed in the
cortex and the hippocampus. MMP-9 levels were unchanged in the
investigated brain regions. Immunohistochemically, MMP-2 was
localized primarily in astrocytes and Microglia
cells, whereas MMP-9 was predominantly neuronal. Levels of TIMP-1,
an endogenous tissue inhibitor of MMPs, were significantly elevated
in the substantia nigra, but not in the cortex and hippocampus.
TIMP-2 levels were unchanged in PD. To investigate whether increased
TIMP-1 levels in the substantia nigra might be due to increased
MMP-1 expression, we measured MMP-1 levels using Western blots.
MMP-1 levels were unchanged in PD cases compared to controls.
Together, these data show alterations of MMP-2 and TIMP-1 in the
substantia nigra of PD, consistent with the possibility that
alterations in MMPs/TIMPs may contribute to disease pathogenesis
McGeer PL, Yasojima K, McGeer EG (2002) Association of
interleukin-1 beta polymorphisms with idiopathic Parkinson's
disease. Neurosci.Lett. 326:67-69
Abstract: Activated Microglia
surround degenerating substantia nigra neurons in Parkinson's
disease (PD). Such Microglia
produce high levels of interleukin-1 beta (IL-1 beta) and
interleukin-1 alpha (IL-1 alpha). T and C alleles exist for the IL-1
beta-511 regulatory region as well as for the IL-1 alpha-889
regulatory region. The T genotypes of both have been reported to
increase the risk of Alzheimer's disease (AD) (Arch. Neurol. 58
(2001) 1790). Since the lesions of PD and AD have similar
neuroinflammatory characteristics (Neurology 38 (1988) 1285), we
genotyped 100 PD and 100 control postmortem brains for the same
polymorphisms. We found a significant increase of the IL-1 beta T
genotype in PD cases compared with controls (chi(2)=9.65, P=0.0019).
A significant increase was not found for the IL-alpha T genotype
(chi(2)=1.32, P=0.23), although there was a trend towards more
frequent expression of the T allele
Michel PP, Hirsch EC, Agid Y (2002) [Parkinson's
disease: cell death mechanisms]. Rev.Neurol.(Paris)
158:24-32
Abstract: Parkinson
disease is a neurodegenerative disorder of aging characterized by a
selective and progressive loss of dopaminergic neurons within the
substantia nigra. The diagnosis of the disease is made when neuronal
cell loss exceeds 50 p. cent indicating that the degenerative
process started well before the onset of the first clinical
symptoms. Three populations of dopaminergic neurons seem to coexist
in the substantia nigra of Parkinsonian
patients; (1) senescent neurons that are still spared by the
pathological process; (2) sick neurons exhibiting generally a
preserved morphology but showing evidence of biochemical and
metabolic abnormalities; (3) neurons which have entered into a final
state of agony and exhibit the hallmarks of apoptosis, a controlled
form of cell death that requires the activation of a particular type
of proteases, caspases. In the inherited forms of the disease that
are caused by mutations of genes encoding the Parkin,
alpha-synuclein and UCHL-1 proteins, the degenerative process
results from the dysfunction of an enzymatic complex of proteolysis,
the proteasome. This probably leads to the intracellular
accumulation of abnormal proteins that become deleterious for
dopaminergic neurons. In the sporadic forms of the disease that are
the most frequent, causes of the cell demise remain still unknown
but neurodegeneration might also result from a decreased activity of
the proteasome. A defect in the detoxification of reactive oxygen
species or an energy failure caused by inhibition of the
mitochondrial respiratory chain, at the complex I level, are other
hypothesis that are frequently mentioned. Finally, activated glial
cells (astrocytes and Microglia)
located around the degenerating dopaminergic neurons might also
intervene in the mechanism of degeneration by perpetuating or even
amplifying the primary neuronal insult. Proinflammatory cytokines
acting on cell death membrane receptors and diffusable messengers
such as nitric oxide could be part of this process
Michel PP, Hirsch EC, Agid Y (2002) [Parkinson
disease: mechanisms of cell death]. Rev.Neurol.(Paris) 158 Spec no
1:S24-S32
Abstract: Parkinson
disease is a neurodegenerative disorder of aging characterized by a
selective and progressive loss of dopaminergic neurons within the
substantia nigra. The diagnosis of the disease is made when neuronal
cell loss exceeds 50 p. 100 indicating that the degenerative process
started well before the onset of the first clinical symptoms. Three
populations of dopaminergic neurons seem to coexist in the
substantia nigra of Parkinsonian
patients; (1) senescent neurons that are still spared by the
pathological process; (2) sick neurons exhibiting generally a
preserved morphology but showing evidence of biochemical and
metabolic abnormalities; (3) neurons which have entered into a final
state of agony and exhibit the hallmarks of apoptosis, a controlled
form of cell death that requires the activation of a particular type
of proteases, caspases. In the inherited forms of the disease that
are caused by mutations of genes encoding the Parkin,
alpha-synuclein and UCHL-1 proteins, the degenerative process
results from the dysfunction of an enzymatic complex of proteolysis,
the proteasome. This probably leads to the intracellular
accumulation of abnormal proteins that become deleterious for
dopaminergic neurons. In the sporadic forms of the disease that are
the most frequent, causes of the cell demise remain still unknown
but neurodegeneration might also result from a decreased activity of
the proteasome. A defect in the detoxification of reactive oxygen
species or an energy failure caused by inhibition of the
mitochondrial respiratory chain, at the complex I level, are other
hypothesis that are frequently mentioned. Finally, activated glial
cells (astrocytes and Microglia)
located around the degenerating dopaminergic neurons might also
intervene in the mechanism of degeneration by perpetuating or even
amplifying the primary neuronal insult. Proinflammatory cytokines
acting on cell death membrane receptors and diffusable messengers
such as nitric oxide could be part of this process
Orr CF, Rowe DB, Halliday GM (2002) An inflammatory review of
Parkinson's disease.
Prog.Neurobiol. 68:325-340
Abstract: The symptoms of Parkinson's
disease (PD) were first described nearly two centuries ago and its
characteristic pathology identified nearly a century ago, yet its
pathogenesis is still poorly understood. Parkinson's
disease is the most prevalent neurodegenerative movement disorder
and research into its pathogenesis recently accelerated following
the identification of a number of causal genetic mutations. The
mutant gene products all cause dysfunction of the
ubiquitin-proteosome system, identifying protein modification and
degradation as critical for pathogenesis. Modified non-degraded
intracellular proteins accumulate in certain neuronal populations in
all forms of the disease. However, neuronal degeneration is more
highly selective and associates with substantial activation of
Microglia,
the inflammatory cells of the brain. We review the current change in
thinking regarding the role of Microglia
in the brain in the context of Parkinson's
disease and animal models of the disease. Comparison of the cellular
tissue changes across a number of animal models using diverse
stimuli to mimic Parkinson's
disease reveals a consistent pattern implicating Microglia
as the effector for the selective degeneration of dopaminergic
neurons. While previous reviews have concentrated on the
intracellular neuronal changes in Parkinson's
disease, we highlight the cell to cell interactions and immune
regulation critical for neuronal homeostasis and survival in
Parkinson's disease
Ryu JK, Shin WH, Kim J, Joe EH, Lee YB, Cho KG, Oh YJ, Kim
SU, Jin BK (2002) Trisialoganglioside GT1b induces in vivo
degeneration of nigral dopaminergic neurons: role of Microglia.
Glia 38:15-23
Abstract: We recently showed that
trisialoganglioside (GT1b) induces cell death of dopaminergic
neurons in rat mesencephalic cultures (Chung et al., Neuroreport
12:611-614, 2001). The present study examines the in vivo neurotoxic
effects of GT1b on dopaminergic neurons in the substantia nigra (SN)
of Sprague-Dawley rats. Seven days after GT1b injection into the SN,
immunocytochemical staining of SN tissue revealed death of nigral
neurons, including dopaminergic neurons. Additional immunostaining
using OX-42 and OX-6 antibodies showed that GT1b-activated Microglia
were present in the SN where degeneration of nigral neurons was
found. Western blot analysis and double-labeled immunohistochemistry
showed that inducible nitric oxide synthase (iNOS) was expressed in
the SN, where its levels were maximal at 8 h post-GT1b injection,
and that iNOS was localized exclusively within Microglia.
GT1b-induced loss of dopaminergic neurons in the SN was partially
inhibited by N(G)-nitro-L-arginine methyl ester hydrochloride, an
NOS inhibitor. Our results indicate that in vivo neurotoxicity of
GT1b against nigral dopaminergic neurons is at least in part
mediated by nitric oxide released from activated Microglia.
Because GT1b exists abundantly in central nervous system neuronal
membranes, our data support the hypothesis that immune-mediated
events triggered by endogenous compounds such as GT1b could
contribute to the initiation and/or the progression of dopaminergic
neuronal cell death that occurs in Parkinson's
disease
Sriram K, Matheson JM, Benkovic SA, Miller DB, Luster MI,
O'Callaghan JP (2002) Mice deficient in TNF receptors are protected
against dopaminergic neurotoxicity: implications for Parkinson's
disease. FASEB J. 16:1474-1476
Abstract: The pathogenic
mechanisms underlying idiopathic Parkinson's
disease (PD) remain enigmatic. Recent findings suggest that
inflammatory processes are associated with several neurodegenerative
disorders, including PD. Enhanced expression of the proinflammatory
cytokine, tumor necrosis factor (TNF)-alpha, has been found in
association with glial cells in the substantia nigra of patients
with PD. To determine the potential role for TNF-alpha in PD, we
examined the effects of the
1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), a dopaminergic
neurotoxin that mimics some of the key features associated with PD,
using transgenic mice lacking TNF receptors. Administration of MPTP
to wild-type (+/+) mice resulted in a time-dependent expression of
TNF-alpha in striatum, which preceded the loss of dopaminergic
markers and reactive gliosis. In contrast, transgenic mice carrying
homozygous mutant alleles for both the TNF receptors (TNFR-DKO), but
not the individual receptors, were completely protected against the
dopaminergic neurotoxicity of MPTP. The data indicate that the
proinflammatory cytokine TNF-alpha is an obligatory component of
dopaminergic neurodegeneration. Moreover, because TNF-alpha is
synthesized predominantly by Microglia
and astrocytes, our findings implicate the participation of glial
cells in MPTP-induced neurotoxicity. Similar mechanisms may underlie
the etiopathogenesis of PD
Tomas-Camardiel M, Sanchez-Hidalgo MC, Sanchez del Pino MJ,
Navarro A, Machado A, Cano J (2002) Comparative study of the
neuroprotective effect of dehydroepiandrosterone and
17beta-estradiol against 1-methyl-4-phenylpyridium toxicity on rat
striatum. Neuroscience 109:569-584
Abstract: The effects of
dehydroepiandrosterone, estradiol and testosterone on
1-methyl-4-phenylpyridium (MPP+)-induced neurotoxicity of the
nigrostriatal dopaminergic system were examined in rat. They were
subjected to a unilateral intrastriatal infusion of the following
treatment conditions: MPP+ alone or co-injection of MPP+ plus each
hormone. Four days after injection, concentrations of dopamine and
their metabolites were determined from the corpus striatum. To
corroborate the neurochemical data an immunohistochemical analysis
of tyrosine hydroxylase-immunoreactive fibers and
acetylcholinesterase histochemistry in the striatum was performed.
Moreover, we performed a dose-response study of the three hormones
on the high-affinity dopamine transport system in rat striatal
synaptosomes.Rats co-injected within the striatum with MPP+ and
either dehydroepiandrosterone or estradiol had significantly greater
concentrations of dopamine and less tyrosine
hydroxylase-immunoreactive fibers and acetylcholinesterase fiber
density loss compared with their respective controls. In addition, 4
days after injection, the brain was fixed and cut into coronal
sections, and was immunostained with major histocompatibility
complex class II antigens for activated Microglia,
and glial fibrillary acidic protein for activated astrocytes.
Dehydroepiandrosterone also attenuated Microglial
cell activation. In contrast, testosterone showed reductions in
dopamine concentrations similar to those obtained by MPP+. The
protective effect of dehydroepiandrosterone against the MPP+
neurotoxic dopaminergic system may be produced by its partial
prevention of MPP+ inhibition of NADH oxidase activity, whereas the
estradiol may function as a neuroprotectant by reducing the uptake
of MPP+ into dopaminergic neurons.Our findings we suggest indicate
that dehydroepiandrosterone and estradiol by a non-genomic effect
may have an important modulatory action, capable of attenuating
degeneration within the striatum, and in this way serve as
neuroprotectants of the nigrostriatal dopaminergic system
Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth
C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of
Microglial
activation is neuroprotective in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of
Parkinson disease.
J.Neurosci. 22:1763-1771
Abstract:
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the
nigrostriatal dopaminergic pathway as seen in Parkinson's
disease (PD), a common neurodegenerative disorder with no effective
protective treatment. Consistent with a role of glial cells in PD
neurodegeneration, here we show that minocycline, an approved
tetracycline derivative that inhibits Microglial
activation independently of its antimicrobial properties, mitigates
both the demise of nigrostriatal dopaminergic neurons and the
formation of nitrotyrosine produced by MPTP. In addition, we show
that minocycline not only prevents MPTP-induced activation of
Microglia
but also the formation of mature interleukin-1beta and the
activation of NADPH-oxidase and inducible nitric oxide synthase
(iNOS), three key Microglial-derived
cytotoxic mediators. Previously, we demonstrated that ablation of
iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that
iNOS is not the only Microglial-related
culprit implicated in MPTP-induced toxicity because mutant
iNOS-deficient mice treated with minocycline are more resistant to
this neurotoxin than iNOS-deficient mice not treated with
minocycline. This study demonstrates that Microglial-related
inflammatory events play a significant role in the MPTP neurotoxic
process and suggests that minocycline may be a valuable
neuroprotective agent for the treatment of PD
Wu dC, Tieu K, Cohen O, Choi DK, Vila M, Jackson-Lewis V,
Teismann P, Przedborski S (2002) Glial cell response: A pathogenic
factor in Parkinson's
disease. J.Neurovirol. 8:551-558
Abstract: Parkinson's
disease (PD) is a common neurodegenerative disorder characterized by
the progressive loss of dopaminergic neurons in the substantia nigra
pars compacta (SNpc). The loss of these neurons is associated with a
glial response composed mainly of activated Microglial
cells and, to a lesser extent, of reactive astrocytes. This glial
response may be the source of trophic factors and can protect
against reactive oxygen species and glutamate. Alternatively, this
glial response can also mediate a variety of deleterious events
related to the production of pro-oxidant reactive species,
proinflammatory prostaglandin, and cytokines. In this review, the
authors discuss the potential protective and deleterious effects of
glial cells in the SNpc of PD and examine how these factors may
contribute to the pathogenesis of this disease
Armstrong RJ, Harrower TP, Hurelbrink CB, McLaughin M,
Ratcliffe EL, Tyers P, Richards A, Dunnett SB, Rosser AE, Barker RA
(2001) Porcine neural xenografts in the immunocompetent rat: immune
response following grafting of expanded neural precursor cells.
Neuroscience 106:201-216
Abstract: Intracerebral neural
xenografts elicit a host immune response that results in their rapid
rejection. This forms a key barrier to the therapeutic use of
xenogeneic tissue transplantation for conditions such as Parkinson's
disease. The current study sought to provide insight into the
cellular components of donor cell suspensions that are important in
stimulating the host rejection response and thereby to suggest
rational manipulations of xenogeneic donor tissue that might
ultimately enhance its clinical utility. The neural stem cell
mitogens, epidermal growth factor and fibroblast growth factor-2,
have been used to isolate and expand populations of primordial
neural precursor cells from the embryonic pig brain. The immune
response elicited by these cells on transplantation into the
non-immunosuppressed rat has been fully characterised.In the first
experiments, expanded neural precursors were grafted into the
hemi-Parkinsonian,
non-immunosuppressed Sprague-Dawley rat and graft status and host
response examined 10, 21, 35 and 60 days post-transplantation. While
equivalent primary tissue grafts were completely eliminated at 35
days, grafts of expanded neural precursors with healthy
neurofilament-positive projections were present at all time-points,
and two large grafts remained even at 60 days. Some grafts appeared
to elicit minimal host immune responses at the time-points they were
examined, although most did appear to be undergoing a rejection
process since a co-ordinated response involving host cytotoxic
T-lymphocytes, Microglia/macrophages,
immunoglobulin M and complement could be demonstrated to varying
degrees.Subsequent experiments went on to demonstrate further that
expanded precursor populations and primary tissue suspensions
differed in their immunogenic profile. Firstly, when primary tissue
was injected intraperitoneally into immunocompetent rats a vigorous
primary humoral response was generated. No such response was
detected following injection of expanded neural precursors.
Secondly, flow cytometric analysis revealed small but significant
levels of class II porcine major histocompatibility complex
expression in primary cell suspensions but no such expression in
expanded precursor populations.The results of this study therefore
demonstrate that the immunogenicity of porcine neural cell
suspensions used for intracerebral grafting is reduced when neural
stem cell mitogens are used to expand precursor cells. The
implications of these findings in the development of novel
xenogeneic cellular therapies for neurodegenerative conditions such
as Parkinson's disease are
discussed
Berg D, Gerlach M, Youdim MB, Double KL, Zecca L, Riederer P,
Becker G (2001) Brain iron pathways and their relevance to
Parkinson's disease.
J.Neurochem. 79:225-236
Abstract: A central role of iron in the
pathogenesis of Parkinson's
disease (PD), due to its increase in substantia nigra pars compacta
dopaminergic neurons and reactive Microglia
and its capacity to enhance production of toxic reactive oxygen
radicals, has been discussed for many years. Recent transcranial
ultrasound findings and the observation of the ability of iron to
induce aggregation and toxicity of alpha-synuclein have reinforced
the critical role of iron in the pathogenesis of nigrostriatal
injury. Presently the mechanisms involved in the disturbances of
iron metabolism in PD remain obscure. In this review we summarize
evidence from recent studies suggesting disturbances of iron
metabolism in PD at possibly different levels including iron uptake,
storage, intracellular metabolism, release and post-transcriptional
control. Moreover we outline that the interaction of iron with other
molecules, especially alpha-synuclein, may contribute to the process
of neurodegeneration. Because many neurodegenerative diseases show
increased accumulation of iron at the site of neurodegeneration, it
is believed that maintenance of cellular iron homeostasis is crucial
for the viability of neurons
Brevig T, Meyer M, Kristensen T, Zimmer J, Holgersson J
(2001) Xenotransplantation for brain repair: reduction of porcine
donor tissue immunogenicity by treatment with anti-Gal antibodies
and complement. Transplantation 72:190-196
Abstract: BACKGROUND:
Transplantation of embryonic neural tissue is a potential treatment
for Parkinson's disease.
Because human donor material is in short supply, porcine xenografts
are considered a useful alternative. Current immunosuppressive
therapies fail, however, to protect intracerebral neural xenografts
from host CD4 T lymphocytes. To reduce the immunogenicity of porcine
donor tissue, we attempted to remove Microglial
cells with antibodies against the alpha-galactosyl epitope
(Galalpha1,3Galbeta1,4GlcNAc-R), or anti-Gal, and complement, and
studied whether this pretreatment can reduce direct and indirect
T-cell responses to the tissue. METHODS: Brain tissue from
27-day-old pig embryos was dissociated and treated with human
anti-Gal and rabbit complement. The Microglial
content was analyzed by flow cytometry. [3H]thymidine incorporation
in cocultures of the brain cells and purified human CD4 T cells was
used to determine direct T-cell responses. Indirect T-cell responses
were studied by grafting pretreated and control-pretreated (no
anti-Gal) nigral tissue into the lesioned striatum of
immunocompetent rats with 6-hydroxydopamine-induced
hemiParkinsonism.
Amphetamine-induced circling behavior was used to measure graft
function. RESULTS: Anti-Gal and complement reduced the Microglial
content to 11-24% of control and abolished the ability of the brain
cells to induce human CD4 T-cell proliferation. Pretreated nigral
tissue reduced hemiParkinsonism
by more than 50% in five of eight rats at some point during the
10-week follow-up. Rats receiving control-pretreated nigral tissue
did not display this degree of improvement. CONCLUSIONS:
Pretreatment with anti-Gal and complement can reduce the
immunogenicity of porcine neural tissue, and might, therefore, be a
valuable alternative or supplement to immunosuppression in neural
xenotransplantation
Brevig T, Meyer M, Kristensen T, Zimmer J (2001) Neural
xenotransplantation: pretreatment of porcine embryonic nigral tissue
with anti-Gal antibodies and complement is not toxic for the
dopaminergic neurons. Cell Transplant. 10:25-30
Abstract: The
immunogenicity of porcine tissue is a major obstacle to its use as
donor material in xenotransplantation for neurodegenerative
diseases. We are currently evaluating a novel strategy for reducing
the immunogenicity, in which the alpha-galactosyl epitope
(Galalpha1,3Galbeta1,4GlcNAc-R) is used as a target for antibody-
and complement-mediated removal of Microglia.
In the present study, our aim was to determine whether a
pretreatment with antibodies against the alpha-galactosyl epitope
(anti-Gal) and complement would lyse or otherwise damage
dopaminergic neurons in porcine embryonic ventral mesencephalon
(VM), the donor tissue for treatment of Parkinson's
disease by xenotransplantation. Cell suspensions prepared from VM
tissue from 27-day-old pig embryos were incubated with anti-Gal,
purified from normal human serum by affinity chromatography, or
medium only (control), and subsequently with rabbit complement.
After these pretreatments, the cell suspensions were transplanted
into the right striatum of 14 adult rats (two groups of 7 animals).
The animals were sacrificed 20 days after transplantation, the
brains were processed for histology, and the sections were stained
for Nissl substance, porcine neurofilament, tyrosine hydroxylase,
and rat CD45 to determine graft volume, presence of porcine neurons,
content of dopaminergic cells, and leukocyte infiltration,
respectively. The VM tissue pretreated with anti-Gal and complement
gave rise to dopaminergic grafts that were indistinguishable from
those derived from VM tissue given the control pretreatment. In 5 of
the 14 animals, the grafts were infiltrated by host leukocytes, but
in two of these recipients, the infiltration was only minimal. We
conclude that anti-Gal and complement can be applied to porcine
embryonic VM tissue without damaging the dopaminergic neurons and
their precursors
Czlonkowska A, Kurkowska-Jastrzebska I (2001) [Treatment of
neurodegenerative diseases: new perspectives]. Neurol.Neurochir.Pol.
35:147-156
Abstract: The experimental models of neurodegeneration
give a possibility to study the inflammatory reaction that starts in
response to neuronal death. Inflammation consists of Microglial
and astroglial activation, expression of new molecules as cytokines,
adhesion molecules and MHC antigens, and is potentially neurotoxic.
This article is a summary of a few latest studies that investigate
anti-inflammatory agents effect on neuron survival in MPTP mice
model of Parkinson's
disease. Murine model of Parkinson's
disease uses a quite selective toxic effect of MPTP on nigrostriatal
system. MPTP causes degeneration of dopaminergic cells bodies in the
substantia nigra and of their endings in striatum. Our findings show
that anti-inflammatory treatment protects neuronal death. It may
indicate that the inflammation contributes to the dopaminergic
neuron impairment following MPTP intoxication. However this
hypothesis needs further investigation because recent studies
suggest that inflammation may have also a protective effect in
neurodegentration
Fillebeen C, Ruchoux MM, Mitchell V, Vincent S, Benaissa M,
Pierce A (2001) Lactoferrin is synthesized by activated Microglia
in the human substantia nigra and its synthesis by the human
Microglial
CHME cell line is upregulated by tumor necrosis factor alpha or
1-methyl-4-phenylpyridinium treatment. Brain Res.Mol.Brain Res.
96:103-113
Abstract: The presence of the iron-binding protein
lactoferrin (Lf) in some specific areas of the central nervous
system and particularly in the normal human substantia nigra, where
it is found in dopaminergic (DA) neurons and some glial cells, led
us to investigate Lf synthesis in this area. Lf mRNA were identified
using in situ hybridization and found in small ameboid cells. These
cells were identified using immunocytochemistry as activated
Microglia
since they exhibited macrophage markers such as the CD68 and the CR1
antigens. Double immunofluorescent labeling confirmed that the two
Lf immunostained cell populations were activated Microglia
and DA neurons. Since activated Microglia
contained both Lf and its messenger, these cells are the Lf
producing cells. The presence of Lf in DA neurons in which no Lf
messengers were visible, might be due to an endocytosis mechanism,
DA neurons probably internalizing Lf produced in Microglial
cells located in their neighborhood. In neuropathological disorders,
such as Alzheimer's and Parkinson's
diseases, inflammatory process and oxidative stress are events that
contribute to neuronal death. Since Lf concentration increases
during these pathologies, we studied the level of Lf expression
under these different stresses and showed, using RT-PCR, that the
immortalized human embryonic Microglial
CHME cell line produced Lf transcripts under tumor necrosis factor
alpha or 1-methyl-4-phenylpyridinium treatment whereas untreated
cells did not. These data confirm that Lf is produced only when
Microglia
are activated
Fiszer U (2001) Does Parkinson's
disease have an immunological basis? The evidence and its
therapeutic implications. BioDrugs. 15:351-355
Abstract:
Parkinson's disease (PD) is
an age-related neurodegenerative movement disorder of unknown
aetiology. Immune abnormalities have been described in PD including
the occurrence of autoantibodies against neuronal structures and
high numbers of Microglia
cells expressing the histocompatibility glycoprotein human leucocyte
antigen-DR in the substantia nigra. An infectious cause for PD has
been discussed for years. Disturbed cellular and humoral immune
functions in peripheral blood of patients with PD have been also
reported. An elevated gammadelta(+) T cell population and increased
immunoglobulin G immunity in CSF to heat shock proteins have been
found in PD. Cytokines and apoptosis-related proteins were elevated
in the striatum in patients with PD. Activated glial cells may
participate in neuronal cell death in PD by providing toxic
substances. We may conclude that the immune system is involved in
the pathogenesis of PD. However, we are not able to determine
whether the disturbances described above constitute a primary or
secondary phenomenon. Immunomodulatory agents may have important
applications in the development of new therapies for PD
He Y, Appel S, Le W (2001) Minocycline inhibits Microglial
activation and protects nigral cells after 6-hydroxydopamine
injection into mouse striatum. Brain Res. 909:187-193
Abstract:
To determine the role of immune/inflammatory factors in dopaminergic
cell degeneration in Parkinsonian
substantia nigra, we assayed tyrosine hydroxylase (TH)-positive
immunoreactive neuronal numbers with stereologic techniques and
CD11b-positive immunoreactive Microglial
profiles following 6-hydroxydopamine (6-OHDA) injection into
ipsilateral striatum of mice. We further investigated the effect of
minocycline on the inhibition of Microglial
activation and subsequent protection of nigral cells. The relative
number of Microglial
profiles in the substantia nigra (SN) ipsilateral to the injection
increased from 31 to 32% 1-3 days after injection, and increased
further to 55% by 7 days and 59% by 14 days, compared with the
contralateral SN. These changes started prior to the decrease of TH
immunoreactivity of 34% on day 7 and of 42% by day 14. In animals
treated with minocycline, Microglial
activation was inhibited by 47%, and TH positive cells were
protected by 21% at day 14 after 6-OHDA injection, compared with
those Parkinsonian animals
without minocycline treatment. All these results suggest that
Microglial
activation may be involved in the nigral cell degeneration in 6-OHDA
induced Parkinsonian mice
Le W, Rowe D, Xie W, Ortiz I, He Y, Appel SH (2001)
Microglial
activation and dopaminergic cell injury: an in vitro model relevant
to Parkinson's disease.
J.Neurosci. 21:8447-8455
Abstract: Microglial
activation and oxidative stress are significant components of the
pathology of Parkinson's
disease (PD), but their exact contributions to disease pathogenesis
are unclear. We have developed an in vitro model of nigral injury,
in which lipopolysaccharide-induced Microglial
activation leads to injury of a dopaminergic cell line (MES 23.5
cells) and dopaminergic neurons in primary mesencephalic cell
cultures. The Microglia
are also activated by PD IgGs in the presence of low-dose
dopa-quinone- or H(2)O(2)-modified dopaminergic cell membranes but
not cholinergic cell membranes. The activation requires the
Microglial
FCgammaR receptor as demonstrated by the lack of activation with PD
IgG Fab fragments or Microglia
from FCgammaR-/- mice. Although Microglial
activation results in the release of several cytokines and reactive
oxygen species, only nitric oxide and H(2)O(2) appear to mediate the
Microglia-induced
dopaminergic cell injury. These studies suggest a significant role
for Microglia
in dopaminergic cell injury and provide a mechanism whereby
immune/inflammatory reactions in PD could target oxidative injury
relatively specifically to dopaminergic cells
Satoh JI, Kuroda Y (2001) Alpha-synuclein expression is
up-regulated in NTera2 cells during neuronal differentiation but
unaffected by exposure to cytokines and neurotrophic factors.
Parkinsonism.Relat Disord.
8:7-17
Abstract: Increasing evidence has indicated that
proinflammatory cytokines such as TNF-alpha and IL-1beta, produced
by activated Microglia
and astrocytes, play a key role in progressive degeneration of the
nigrostriatal dopaminergic neurons in Parkinson's
disease (PD). Since alpha-synuclein is a major component of Lewy
bodies in PD brains, we studied the constitutive and
cytokine/neurotrophic factor-regulated expression of alpha-synuclein
in cultured human neurons by Northern blot and Western blot
analyses. The constitutive expression of alpha-synuclein mRNA was
identified in a variety of human neural and non-neural cell lines.
The levels of alpha-synuclein expression were elevated markedly in
NTera2 teratocarcinoma cells following retinoic acid-induced
neuronal differentiation, accompanied with an increased expression
of synphilin-1, while they were unaltered in NTera2-derived
differentiated neurons by exposure to TNF-alpha, IL-1beta, BDNF or
GDNF. These results indicate that alpha-synuclein expression in
human neurons is up-regulated during differentiation, but is
unaffected by a panel of cytokines and neurotrophic factors which
are supposed to be involved in the nigral neuronal death and
survival
Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teismann P, Choi
DK, Tieu K, Przedborski S (2001) The role of glial cells in
Parkinson's disease.
Curr.Opin.Neurol. 14:483-489
Abstract: Parkinson's
disease is a common neurodegenerative disorder characterized by the
progressive loss of the dopaminergic neurons in the substantia nigra
pars compacta. The loss of these neurons is associated with a glial
response composed mainly of activated Microglial
cells and, to a lesser extent, of reactive astrocytes. This glial
response may be the source of trophic factors and can protect
against reactive oxygen species and glutamate. Aside from these
beneficial effects, the glial response can mediate a variety of
deleterious events related to the production of reactive species,
and pro-inflammatory prostaglandin and cytokines. This article
reviews the potential protective and deleterious effects of glial
cells in the substantia nigra pars compacta of Parkinson's
disease
Yasojima K, Tourtellotte WW, McGeer EG, McGeer PL (2001)
Marked increase in cyclooxygenase-2 in ALS spinal cord: implications
for therapy. Neurology 57:952-956
Abstract: OBJECTIVE: To
evaluate the hypothesis that cyclooxygenase-2 (COX-2) is linked to
the pathology of ALS by determining whether COX-2 mRNA levels are
upregulated in ALS spinal cord. METHODS: Spinal cord from 11 ALS
cases and 27 controls consisting of 15 cases of Alzheimer disease
(AD), six cases of Parkinson
disease (PD), three cases of cerebrovascular disease, and three
control cases were analyzed. Total RNA was extracted and reverse
transcriptase-PCR analysis performed for the mRNA of COX-2, COX-1,
the Microglial
marker CD11b, and the housekeeping gene cyclophilin. RESULTS: In ALS
compared with non-ALS spinal cord, COX-2 mRNA was upregulated
7.09-fold (p < 0.0001), COX-1 1.14-fold (p = 0.05), and CD11b
1.85-fold (p = 0.0012). COX-2 mRNA levels in AD, PD, cerebrovascular
disease, and control cases were each significantly lower than in ALS
and were not significantly different from each other. Western blots
of the protein products were in general accord with the mRNA data,
with COX-2 protein levels being upregulated 3.79-fold compared with
non-ALS cases (p = 0.015). CONCLUSIONS: The strong upregulation of
COX-2 mRNA in ALS is in accord with studies in the superoxide
dismutase transgenic mouse model in which COX-2 upregulation occurs.
Taken in conjunction with evidence of a neuroprotective effect of
COX-2 inhibitors in certain animal models and in organotypic
cultures, the data are supportive of a possible future role for
COX-2 inhibitors in the treatment of ALS
Grunblatt E, Mandel S, Youdim MB (2000) MPTP and
6-hydroxydopamine-induced neurodegeneration as models for
Parkinson's disease:
neuroprotective strategies. J.Neurol. 247 Suppl 2:II95-102
Abstract:
The etiology of Parkinson's
disease is not known. Nevertheless, a significant body of
biochemical data from human brain autopsy studies and from animal
models points to an ongoing process of oxidative stress in the
substantia nigra, which could initiate dopaminergic
neurodegeneration. It is not known whether oxidative stress is a
primary or secondary event. Oxidative stress, as induced by the
neurotoxins 6-hydroxydopamine and MPTP
(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), has been used in
animal models to investigate the process of neurodegeneration to
facilitate the development of antioxidant, neuroprotective drugs. It
is apparent in these animal models that radical scavengers, iron
chelators, dopamine agonists, nitric oxide synthase inhibitors and
certain calcium channel antagonists provide neuroprotection against
such toxins if given prior to the insult. Furthermore, recent work
from human and animal studies has provided evidence of an
inflammatory process. This expresses itself as proliferation of
activated Microglia
in the substantia nigra, activation and translocation of
transcription factors and neurotrophic factor (NF), kappa-beta and
elevation of cytotoxic cytokines, tumour necrosis factor
(TNF)-alpha, interleukin (IL)-1beta, and IL-6. Both radical
scavengers and iron chelators prevent lipopolysaccharide (LPS) and
iron-induced activation of NF kappa-beta. If an inflammatory
response is involved in Parkinson's
disease, it would be logical to consider antioxidants and the newly
developed, non-steroidal, anti-inflammatory drugs such as
cyclo-oxygenase (COX2) inhibitors as a form of treatment. However,
to date there has been little or no success in the clinical
treatment of neurodegenerative diseases (for example, Parkinson's
disease, ischaemia etc.) where neurons die, while in animal models
the same drugs provide neuroprotection. This may indicate that
either the animal models employed do not reflect the events in
neurodegenerative diseases, or that because neuronal death involves
a cascade of events, a single neuroprotective drug is not effective.
Thus, consideration should be given to multi-neuroprotective drug
therapy in Parkinson's
disease, similar to the approach taken in AIDS and cancer therapy
Grunblatt E, Mandel S, Youdim MB (2000) Neuroprotective
strategies in Parkinson's
disease using the models of 6-hydroxydopamine and MPTP.
Ann.N.Y.Acad.Sci. 899:262-273
Abstract: The etiology of
Parkinson's disease is not
known. Nevertheless a significant body of biochemical data from
human brain autopsy studies and those from animal models point to an
on going process of oxidative stress in the substantia nigra which
could initiate dopaminergic neurodegeneration. It is not known
whether oxidative stress is a primary or secondary event.
Nevertheless, oxidative stress as induced by neurotoxins
6-hydroxydopamine and MPTP
(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been used in
animal models to investigate the process of neurodegeneration with
intend to develop antioxidant neuroprotective drugs. It is apparent
that in these animal models radical scavengers, iron chelators,
dopamine agonists, nitric oxide synthase inhibitors and certain
calcium channel antagonists do induce neuroprotection against such
toxins if given prior to the insult. Furthermore, recent work from
human and animal studies has provided also evidence for an
inflammatory process. This expresses itself by proliferation of
activated Microglia
in the substantia nigra, activation and translocation of
transcription factors, NF kappa-beta and elevation of cytotoxic
cytokines TNF alpha, IL1-beta, and IL6. Both radical scavengers and
iron chelators prevent LPS (lipopolysaccharide) and iron induced
activation of NF kappa-B. If an inflammatory response is involved in
Parkinson's disease it
would be logical to consider antioxidants and the newly developed
non-steroid anti-inflammatory drugs such as COX2 (cyclo-oxygenase)
inhibitors as a form of treatment. However to date there has been
little or no success in the clinical treatment of neurodegenerative
diseases per se (Parkinson's
disease, ischemia etc.), where neurons die, while in animal models
the same drugs produce neuroprotection. This may indicate that
either the animal models employed are not reflective of the events
in neurodegenerative diseases or that because neuronal death
involves a cascade of events, a single neuroprotective drug would
not be effective. Thus, consideration should be given to
multi-neuroprotective drug therapy in Parkinson's
disease, similar to the approach taken in AIDS and cancer therapy
Herrera AJ, Castano A, Venero JL, Cano J, Machado A (2000)
The single intranigral injection of LPS as a new model for studying
the selective effects of inflammatory reactions on dopaminergic
system. Neurobiol.Dis. 7:429-447
Abstract: We have injected
lipopolysaccharide (LPS) into the nigrostriatal pathway of rats in
order to address the role of inflammation in Parkinson's
disease (PD). LPS induced a strong macrophage/Microglial
reaction in Substantia nigra (SN), with a characteristic clustering
of macrophage cells around blood-vessels. The SN was far more
sensitive than the striatum to the inflammatory stimulus. Moreover,
only the dopaminergic neurons of the SN were affected, with no
detectable damage to either the GABAergic or the serotoninergic
neurons. The damage to the DA neurons in the SN was permanent, as
observed 1 year postinjection. Unlike the direct death of
dopaminergic neurons caused by agents as MPP(+) or 6-OHDA, LPS seems
to cause indirect death due to inflammatory reaction. Therefore, we
suggest that the injection of a single dose of LPS within the SN is
an interesting model for studying the selective effects of
inflammatory reaction on dopaminergic system and also potentially
useful for studying PD
Jellinger KA (2000) Cell death mechanisms in Parkinson's
disease. J.Neural Transm. 107:1-29
Abstract: OBJECTIVE: While the
causes of neuronal death in Parkinson's
disease (PD) and other neurodegenerative disorders are still
unknown, several mechanisms are under discussion: programmed vs.
passive cell death (apoptosis vs. necrosis), mainly based on
conflicting results on the rare presence or absence of DNA
fragmentation in substantia nigra neurons using the in situ
DNA-labeling (TUNEL) method. DESIGN/METHODS: In 4 cases of
Parkinson's disease (PD), 2
cases of Dementia with Lewy bodies (DLB) and 3 age-matched controls,
the TUNEL/ISEL method was used to detect DNA fragmentation in
substantia nigra locus coeruleus and cerebral cortex [method by Gold
et al. (1994)]. In addition, immunohistochemistry was performed for
an array of apoptosis-related proteins, i.e. the recently described
apoptosis specific protein cJun/AP1 (ASP), the proto-oncogenes
c-Jun, c-Jun AP1, Bcl2, Bax, Bcl-x, p53, CD 95 (Fas/Apo-1),
activated caspase 3, several heat shock proteins (alpha-B
crystallin, ubiquitin), and alpha-synuclein. RESULTS: None of the
cases of PD, DLB, and controls showed convincing TUNEL-positivity
nor morphologic signs of apoptosis in nigral, locus coeruleus or
cortical neurons with or without Lewy bodies but variable numbers of
TUNEL-positive astrocytes and Microglial
cells in substantia nigra of PD and DLB. There were no significant
differences in the expression of c-Jun, ASP, Bcl-2, Bax, and Bcl-x
in substantia nigra neurons between PD, DLB, and controls nor
between cortical and subcortical neurons with and without Lewy
bodies. No expression of p53, and activated caspase 3, or any of the
examined stress proteins was seen in neurons, while reactive
astroglia and Microglia
were decorated by antibodies to Bcl-2, Bax, alpha-B-crystallin and
less, to Bcl-x and caspase 3. Lewy bodies, dystrophic neurites and
axonal spheroids, all being negative for the applied apoptosis
regulating proteins, showed strong expression of the examined stress
proteins and of alpha-synuclein. CONCLUSIONS: These findings which
are in line with previous results in Alzheimer's disease (Stadelmann
et al., 1998) and Parkinson's
disease (Banati et al., 1999) suggest that mechanisms distinct from
classical apoptosis play a central role in the pathogenesis of PD
and related neurodegenerative diseases. Further studies are
warranted to elucidate the intracellular cascade of events leading
to cell death in these disorders showing slow progression over many
years
Jellinger KA, Stadelmann CH (2000) The enigma of cell death
in neurodegenerative disorders. J.Neural Transm.Suppl21-36
Abstract:
Progressive cell loss in specific neuronal populations is the
pathological hallmark of neurodegenerative diseases, but its
mechanisms remain unresolved. Apoptotic cell death has been
implicated as a major mechanism in Alzheimer disease (AD), Parkinson
disease (PD) and other neurodegenerative disorders. However, DNA
fragmentation in human brain as a sign of neuronal cell injury is
too frequent to account for the continuous loss in these slowly
progressive diseases. In a series of autopsy confirmed cases of AD,
PD, related disorders, and age-matched controls, DNA fragmentation
using the TUNEL method, an array of apoptosis-related proteins
(ARP), proto-oncogenes, and activated caspase-3, the key enzyme of
late-stage apoptosis, were examined. In AD, a considerable number of
hippocampal neurons and glial cells showed DNA fragmentation with a
3- to 6-fold increase related to neurofibrillary tangles and amyloid
deposits, but only 1 in 2.600 to 5.600 neurons displayed apoptotic
morphology and cytoplasmic immunoreactivity for activated caspase-3,
whereas no neurons were labeled in age-matched controls. caspase-3
immunoreactivity was seen in granules of cells with granulovacuolar
degeneration, in around 25% co-localized with early cytoplasmic
deposition of tau-protein. In progressive supranuclear palsy, only
single neurons and several oligodendrocytes in brainstem, some with
tau-deposits, were TUNEL-positive and expressed both ARPs and
activated caspase-3. In PD, dementia with Lewy bodies, multisystem
atrophy (MSA), and corticobasal degeneration, TUNEL-positivity and
expression of ARPs or activated caspase-3 were only seen in
Microglia
and oligodendrocytes with cytoplasmic inclusions, but not in
neurons. These data provide evidence for extremely rare apoptotic
neuronal death in AD and PSP compatible with the progression of
neuronal degeneration in these chronic diseases. Apoptosis mainly
involves reactive Microglia
and oligodendroglia, the latter often involved by deposits of
insoluble fibrillary proteins, while alternative mechanisms of
neuronal death may occur. Susceptible cell populations in a
proapoptotic environment show increased vulnerability towards
metabolic or other noxious factors, with autophagy as a possible
protective mechanism in early stages of programmed cell death. The
intracellular cascade leading to cell death still awaits elucidation
Jellinger KA, Stadelmann C (2000) Mechanisms of cell death in
neurodegenerative disorders. J.Neural Transm.Suppl
59:95-114
Abstract: OBJECTIVE: Progressive cell loss in specific
neuronal populations is the prominent pathological hallmark of
neurodegenerative diseases, but its molecular basis remains
unresolved. Apoptotic cell death has been implicated as a general
mechanism in Alzheimer disease (AD) and other neurodegenerative
disorders. However, DNA fragmention in neurons is too frequent to
account for the continuous loss in these slowly progressive
diseases. MATERIAL AND METHODS: In 9 cases of morphologically
confirmed AD (CERAD criteria, Braak stages 5 or 6), 5 cases of
Parkinson disease (PD) and
3 cases each of Dementia with Lewy bodies (DLB), Progressive
Supranuclear Palsy (PSP), and Multiple System Atrophy (MSA), and 7
age-matched controls, the TUNEL method was used to detect DNA
fragmentation, and immunohistochemistry for an array of
apoptosis-related proteins (ARP), protooncogenes, and activated
caspase-3 were performed. RESULTS: In AD, a considerable number of
hippocampal neurons showed DNA fragmentation with a 3 to 5.7 fold
increase related to neurofibrillary tangles and amyloid deposits,
but only exceptional neurons displayed apoptotic morphology (1 in
1100-5000) and cytoplasmic immunoreactivity for ARPs and activated
caspase-3 (1 in 2600 to 5650 hippocampal neurons), whereas no
neurons were labeled in age-matched controls. Caspase-3
immunoreactivity was seen in granules of granulovacuolar
degeneration, only rarely colocalized with tau-immunoreactivity. In
PD, DLB, and MSA, TUNEL positivity and expression of ARPs or
activated caspase-3 was only seen in Microglia,
rare astrocytes and in oligodendroglia with cytoplasmic inclusions
in MSA, but not in nigral or other neurons with or without Lewy
bodies. In PSP, only single neurons but oligodendrocytes, some with
tau deposits, in brainstem tegmentum and pontine nuclei were
TUNEL-positive and expressed both ARPs and activated caspase-3.
CONCLUSIONS: These data provide evidence for extremely rare
apoptotic neuronal death in AD compatible with the progression of
neuronal degeneration in this chronic disease. In other
neurodegenerative disorders, apoptosis mainly involves Microglia
and oligodendroglia, while alternative mechanisms of neuronal death
may occur. Susceptible cell populations in a proapoptotic
environment show increased vulnerability towards metabolic and other
pathogenic factors, with autophagy as a possible protective
mechanism in early stages of programmed cell death. The
intracellular cascade leading to cell death still awaits elucidation
Knott C, Stern G, Wilkin GP (2000) Inflammatory regulators in
Parkinson's disease: iNOS,
lipocortin-1, and cyclooxygenases-1 and -2. Mol.Cell Neurosci.
16:724-739
Abstract: Degeneration of dopaminergic neurons and
focal gliosis are pathological hallmarks of Parkinson's
disease and although the brain is described as immune-privileged
focal immune reactions surround failing nigral neurons. We examined
the cellular distribution of pro- and anti-inflammatory molecules in
human Parkinsonian and
neurologically normal substantia nigra and caudate-putamen
postmortem. An up-regulation of nitric oxide synthase- and
cyclo-oxygenase-1- and -2-containing amoeboid Microglia
was found in Parkinsonian
but not control nigra. Astroglia contained low levels of these
molecules in both groups. Lipocortin-1-immunoreactive amoeboid
Microglia
were present within the astrocytic envelope of neurons adjacent to
or within glial scars in Parkinsonian
nigra only. Lipocortin-1 is known to have neuroprotective and
anti-inflammatory properties. Up-regulation of nitric oxide synthase
is generally associated with neurodestruction whereas prostaglandin
synthesis may be either neurodestructive or protective. The balance
of these molecules is likely to be decisive in determining neuronal
survival or demise
Larsson LC, Czech KA, Brundin P, Widner H (2000)
Intrastriatal ventral mesencephalic xenografts of porcine tissue in
rats: immune responses and functional effects. Cell Transplant.
9:261-272
Abstract: Transplantation of neural tissue from other
species has the potential to improve function in patients with
neurodegenerative disorders. We investigated the functional effects
of embryonic porcine dopaminergic neurons transplanted in a rat
model of Parkinson's
disease and the immune responses to the grafts in immunosuppressed
and nonimmunosuppressed hosts. Twenty-three rats with unilateral
6-hydroxydopamine lesions received dissociated, 27-day-old embryonic
porcine ventral mesencephalic tissue in the right striatum. Eighteen
rats received cyclosporine (10 mg/kg, IP, daily) during the whole
period of 14 weeks, in combination with prednisolone (20 mg/kg, IP,
daily) the first 4 days. Five rats served as nonimmunosuppressed
controls. All rats were tested for amphetamine-induced rotational
behavior at 3-week intervals. Two immunosuppressed rats were
excluded due to severe side effects of the treatment. Functional
recovery was seen in 9 of 16 immunosuppressed rats at 12 weeks. Six
animals remained functionally recovered at 14 weeks and contained an
average of 5750+/-1450 (SEM) dopaminergic neurons. Between 9 and 14
weeks, three immunosuppressed rats rejected their grafts, based on
rotation scores and immunohistochemical demonstration of cell
infiltrates. One additional immunosuppressed rat showed evidence of
ongoing rejection at 14 weeks. The striata in animals with ongoing
or recent rejection contained large numbers of CD4- and CD8-positive
lymphocytes, NK cells, macrophages, and Microglia
cells, whereas scar tissue was found in rats with grafts rejected at
earlier time points (n = 11). Embryonic porcine ventral
mesencephalic tissue matures in the adult rat striatum, reinnervates
the host brain, and restores behavioral defects. Immunosuppressive
treatment was necessary for long-term graft survival and functional
recovery, but did not sufficiently protect from rejection
mechanisms. Porcine neural tissue is an interesting alternative to
embryonic human tissue for intracerebral transplantation in
neurodegenerative diseases. However, to achieve stable graft
survival in discordant xenogeneic combinations, an appropriate
immunosuppressive treatment or donor tissue modifications are needed
Lee CK, Weindruch R, Prolla TA (2000) Gene-expression profile
of the ageing brain in mice. Nat.Genet. 25:294-297
Abstract:
Ageing of the brain leads to impairments in cognitive and motor
skills, and is the major risk factor for several common neurological
disorders such as Alzheimer disease (AD) and Parkinson
disease (PD). Recent studies suggest that normal brain ageing is
associated with subtle morphological and functional alterations in
specific neuronal circuits, as opposed to large-scale neuronal loss.
In fact, ageing of the central nervous system in diverse mammalian
species shares many features, such as atrophy of pyramidal neurons,
synaptic atrophy, decrease of striatal dopamine receptors,
accumulation of fluorescent pigments, cytoskeletal abnormalities,
and reactive astrocytes and Microglia.
To provide the first global analysis of brain ageing at the
molecular level, we used oligonucleotide arrays representing 6,347
genes to determine the gene-expression profile of the ageing
neocortex and cerebellum in mice. Ageing resulted in a
gene-expression profile indicative of an inflammatory response,
oxidative stress and reduced neurotrophic support in both brain
regions. At the transcriptional level, brain ageing in mice displays
parallels with human neurodegenerative disorders. Caloric
restriction, which retards the ageing process in mammals,
selectively attenuated the age-associated induction of genes
encoding inflammatory and stress responses
Mirza B, Hadberg H, Thomsen P, Moos T (2000) The absence of
reactive astrocytosis is indicative of a unique inflammatory process
in Parkinson's disease.
Neuroscience 95:425-432
Abstract: Virtually any neurological
disorder leads to activation of resident Microglia
and invasion of blood-borne macrophages, which are accompanied by an
increase in number and change in phenotype of astrocytes, a
phenomenon generally termed reactive astrocytosis. One of the
functions attributed to activation of astrocytes is thought to
involve restoration of tissue damage. Hitherto, the role of
astrocytes in the inflammatory reaction occurring in Parkinson's
disease has not received much attention. In the present study, we
examined the inflammatory events in autopsies of the substantia
nigra and putamen from Parkinson's
disease patients using age-matched autopsies from normal patients as
controls. In the substantia nigra, activation of Microglia
was consistently observed in all Parkinson's
disease autopsies as verified from immunohistochemical detection of
CR3/43 and ferritin. Activation of resident Microglia
was not observed in the putamen. No differences were observed
between controls and Parkinson's
disease autopsies from the substantia nigra and putamen, in terms of
distribution, cellular density or cellular morphology of astrocytes
stained for glial fibrillary acidic protein or metallothioneins I
and II, the latter sharing high affinity for metal ions and known to
be induced in reactive astrocytes, possibly to exert anti-oxidative
effects. Together, these findings indicate that the inflammatory
process in Parkinson's
disease is characterized by activation of resident Microglia
without reactive astrocytosis, suggesting that the progressive loss
of dopaminergic neurons in Parkinson's
disease is an ongoing neurodegenerative process with a minimum of
involvement of the surrounding nervous tissue. The absence of
reactive astrocytosis in Parkinson's
disease contrasts what follows in virtually any other neurological
disorder and may indicate that the inflammatory process in
Parkinson's disease is a
unique phenomenon
Ogawa K, Yamada T, Tsujioka Y, Taguchi J, Takahashi M, Tsuboi
Y, Fujino Y, Nakajima M, Yamamoto T, Akatsu H, Mitsui S, Yamaguchi N
(2000) Localization of a novel type trypsin-like serine protease,
neurosin, in brain tissues of Alzheimer's disease and Parkinson's
disease. Psychiatry Clin.Neurosci. 54:419-426
Abstract: Neurosin,
a novel type of trypsin-like serine protease, has been shown to be
preferentially expressed in human brain by northern blotting. We
examined neurosin immunolabeling in the brains of neurologically
normal persons and patients with Alzheimer's disease (AD) and with
Parkinson's disease. We
also identified the expression of the mRNA for neurosin by in situ
hybridization histochemistry and reverse transcription-polymerase
chain reaction (RT-PCR). The neurosin antibody stained all of the
nuclei of various cell types. In neurons, there was also staining of
neuronal cytoplasm, nucleoli and their processes. In AD, staining of
neurons with processes was rare in the damaged areas. Some senile
plaques, extracellular tangles and Lewy bodies were also positive
for neurosin. Expression of the mRNA for neurosin was seen in
neurons in the gray matter, and in Microglial
cells in the white matter. In AD, the intensity of the signal for
neurosin mRNA in the gray matter was decreased compared with normal
control brains. The relative levels of neurosin mRNA in AD brains,
measured by RT-PCR, were lower than those in controls. These results
suggest that in human brain neurosin plays various physiological
roles, and that in AD this molecule, like other serine proteases,
may have a role in the degradation of such substances as
beta-amyloid protein
Rozemuller AJ, Eikelenboom P, Theeuwes JW, Jansen Steur EN,
de Vos RA (2000) Activated Microglial
cells and complement factors are unrelated to cortical Lewy bodies.
Acta Neuropathol.(Berl) 100:701-708
Abstract: Inflammatory
mechanisms have been demonstrated in Alzheimer's disease (AD) but
their presence in other neurodegenerative disorders is not well
documented. Complement factors and activated Microglia
have been reported in the substantia nigra of Parkinson's
disease (PD). In the present study we investigated the cingulate
gyrus of 25 autopsied patients with clinically and
neuropathologically well-documented PD, with or without dementia,
for the presence of (activated) Microglial
cells and their relation with Lewy body (LB)-bearing neurons. In
addition, we studied the presence of complement factors in LBs. Of
the 25 patient, 15 were clinically demented, fulfilling criteria for
dementia with LBs (DLB); 7 also fulfilled CERAD morphological
criteria for probable or definite Alzheimer type of dementia.
Microglia
clustering was seen around congophilic plaques with or without tau
pathology. Microglial
cells were not associated with LB-bearing neurons or noncongophilic
plaques. The cortex of DLB patients without AD plaques did not show
more Microglial
cells than the cortex of non-demented controls. The number of
Microglia
was the lowest in young control patients who died immediately after
trauma. Complement factor C3d was occasionally seen in diffusely
ubiquinated neurons but late complement factors were not detected in
these neurons. Double staining for complement and alpha-synuclein
was negative, suggesting the absence of complement in LBs. In
contrast, AD plaques in the same sections showed complement factors
C3c, C3d, C1q and C5-9. In conclusion, we have found no evidence
that inflammatory mechanism are involved in LB formation in cerebral
cortex
Chang JY, Liu LZ (1999) Manganese potentiates nitric oxide
production by Microglia.
Brain Res.Mol.Brain Res. 68:22-28
Abstract: Manganese toxicity
has been associated with clinical symptoms of neurotoxicity which
are similar to the symptoms observed in Parkinson's
disease. Earlier reports indicated that reactive Microglia
was present in the substantia nigra of patients with Parkinson's
disease. Using N9 Microglial
cells, the current study was designed to determine whether high
levels of manganese were associated with Microglial
activation. Results indicated that manganese significantly increased
the bacterial lipopolysaccharide-induced nitric oxide production.
This potent activity of manganese was not shared by other transition
metals tested, including iron, cobalt, nickel, copper and zinc.
Immunohistochemical staining and Western blot analysis indicated
that manganese increased the cellular production of inducible nitric
oxide synthase. Northern blot analysis indicated that manganese
likely increased iNOS gene transcription since this agent increased
the mRNA level of the inducible nitric oxide synthase. In contrast
to other transition metals tested, manganese did not appear to be
cytotoxic to Microglial
cells. These results suggested that manganese could induce sustained
production of neurotoxic nitric oxide by activated Microglial
cells, which might cause detrimental consequences to surrounding
neurons
Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C,
Peterson DW (1999) Association of circulating TNF-alpha and IL-6
with ageing and Parkinsonism.
Acta Neurol.Scand. 100:34-41
Abstract: INTRODUCTION: We propose
that the increase in TNF-alpha and IL-6 in the brain in idiopathic
Parkinsonism is in response
to a peripheral immune/ inflammatory process, so ubiquitous as to be
responsible for the resemblance between ageing and Parkinsonism.
METHODS: Circulating cytokine was measured in 78 subjects with
idiopathic Parkinsonism and
140 without, aged 30 to 90 years, all obeying inclusion/exclusion
criteria. RESULTS: Serum TNF-alpha increased (P<0.0001) by 1.37
(95% CI 0.75, 2.00)% x y(-1), IL-6 by 2.63 (1.75, 3.52) (P<0.0005).
TNF-alpha appeared elevated in Parkinsonians
whose postural and psychomotor responses were abnormal, being
suppressed where they were normal: trends which contrasted with
those in controls (P = 0.015 and 0.05, respectively). Parkinsonism
appeared (P = 0.08) to have an effect on IL-6, equivalent to that of
>10 years of ageing (28(-3, 69)%), but was not immediately
related to between-subject differences in performance. CONCLUSION:
Ageing and pathogenetic insult may be confounded, age being a
progression, not a risk, factor
Hironishi M, Ueyama E, Senba E (1999) Systematic expression
of immediate early genes and intensive astrocyte activation induced
by intrastriatal ferrous iron injection. Brain Res.
828:145-153
Abstract: The potential role(s) of transitional
metals such as iron have been implicated in neurodegeneration
through biochemical processes, particularly oxidative stress. We
injected ferrous chloride (FeCl2) and ferric chloride (FeCl3) into
the striatonigral system of Sprague-Dawley rats to investigate the
biological and toxic effects of ferrous iron in the central nervous
system. When FeCl2 was injected into the ventral midbrain, rats
showed a characteristic behavior which indicated ipsilateral
dopaminergic hyperactivity. FeCl2 injection into the striatum
induced a dose-dependent damage, the activation of astrocytes and
recruitment of macrophage/Microglia
at the injected site. Interestingly, the activation of astrocytes
was also observed in the anatomically remote areas such as the
ipsilateral subthalamic nucleus and pars reticulata of the
substantia nigra after 1 week. Expression of immediate early genes
(IEGs; c-fos and NGFI-A) was observed in the cortex, thalamic
nuclei, subthalamic nucleus, pars reticulata of the substantia
nigra, lateral and medial geniculate bodies on the ipsilateral side
from 3 to 15 h after FeCl2 injection. Pre-treatment with dimethyl
sulfoxide, a hydroxyl radical scavenger, prevented FeCl2-induced
expression of IEGs in the thalamic nuclei and geniculate bodies, but
not in the cerebral cortex. On the other hand, the effects of FeCl3
were faint and limited on IEGs expression and tissue damage. These
results suggest that ferrous iron affects the nervous system
vigorously, possibly yielding free radicals such as hydroxyl
radicals, and could be one of the important candidates for
neurodegenerative diseases under the state in which acclimating
systems for iron toxicity are disrupted
Hunot S, Dugas N, Faucheux B, Hartmann A, Tardieu M, Debre P,
Agid Y, Dugas B, Hirsch EC (1999) FcepsilonRII/CD23 is expressed in
Parkinson's disease and
induces, in vitro, production of nitric oxide and tumor necrosis
factor-alpha in glial cells. J.Neurosci. 19:3440-3447
Abstract:
Oxidative stress is thought to be involved in the mechanism of nerve
cell death in Parkinson's
disease (PD). Among several toxic oxidative species, nitric oxide
(NO) has been proposed as a key element on the basis of the
increased density of glial cells expressing inducible nitric oxide
synthase (iNOS) in the substantia nigra (SN) of patients with PD.
However, the mechanism of iNOS induction in the CNS is poorly
understood, especially under pathological conditions. Because
cytokines and FcepsilonRII/CD23 antigen have been implicated in the
induction of iNOS in the immune system, we investigated their role
in glial cells in vitro and in the SN of patients with PD and
matched control subjects. We show that, in vitro, interferon-gamma
(IFN-gamma) together with interleukin-1beta (Il-1beta) and tumor
necrosis factor-alpha (TNF-alpha) can induce the expression of CD23
in glial cells. Ligation of CD23 with specific antibodies resulted
in the induction of iNOS and the subsequent release of NO. The
activation of CD23 also led to an upregulation of TNF-alpha
production, which was dependent on NO release. In the SN of PD
patients, a significant increase in the density of glial cells
expressing TNF-alpha, Il-1beta, and IFN-gamma was observed.
Furthermore, although CD23 was not detectable in the SN of control
subjects, it was found in both astroglial and Microglial
cells in Parkinsonian
patients. Altogether, these data demonstrate the existence of a
cytokine/CD23-dependent activation pathway of iNOS and of
proinflammatory mediators in glial cells and their involvement in
the pathophysiology of PD
Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski
A, Czlonkowska A (1999) MHC class II positive Microglia
and lymphocytic infiltration are present in the substantia nigra and
striatum in mouse model of Parkinson's
disease. Acta Neurobiol.Exp.(Wars.) 59:1-8
Abstract: We have
studied MHC class II antigen expression and lymphocytic infiltration
during dopaminergic neurone degeneration produced by intoxication
with 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP). Microglial
activation was observed in the striatum and in the substantia nigra
(SN) in this model. We noticed a marked increase of MHC class II
antigen expression on Microglia
and T-cell recruitment in these regions after MPTP treatment.
B-lymphocytes were not observed. T-cell infiltration predominantly
consisted of CD8+ cells at every time point but CD4+ cells were
present too. More than a half of the observed lymphocytes showed
strong staining of CD44 antigen. Our findings suggest a possible
immune system involvement in the pathological process following MPTP
intoxication
Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila
M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S (1999)
Inducible nitric oxide synthase stimulates dopaminergic
neurodegeneration in the MPTP model of Parkinson
disease. Nat.Med. 5:1403-1409
Abstract: MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic
neurons as seen in Parkinson
disease. Here we show that after administration of MPTP to mice,
there was a robust gliosis in the substantia nigra pars compacta
associated with significant upregulation of inducible nitric oxide
synthase (iNOS). These changes preceded or paralleled MPTP-induced
dopaminergic neurodegeneration. We also show that mutant mice
lacking the iNOS gene were significantly more resistant to MPTP than
their wild-type littermates. This study demonstrates that iNOS is
important in the MPTP neurotoxic process and indicates that
inhibitors of iNOS may provide protective benefit in the treatment
of Parkinson disease
Renkawek K, Stege GJ, Bosman GJ (1999) Dementia, gliosis and
expression of the small heat shock proteins hsp27 and alpha
B-crystallin in Parkinson's
disease. Neuroreport 10:2273-2276
Abstract: Cognitive impairment
and dementia are common in the later stages of Parkinson's
disease (PD). Neuropathological examination of demented PD (PDD)
patients often reveals changes that are typical of Alzheimer's
disease (AD). In AD, there is a massive reactive gliosis and
increased expression of the small heat shock proteins (hsp) hsp27
and alpha B-crystallin. Since these proteins are characteristic for
reactive astrocytes in AD, we investigated their expression in the
brains of PDD patients. The results were compared with those
obtained in the brains of non-demented PD patients. We found (1) no
detectable expression of hsp in PD without dementia, and low
expression in PD with mild dementia; (2) reactive gliosis and
increased expression of hsp in the cortex of PDD brains; (3) a
strong association between hsp immunoreactivity and the severity of
the AD-specific changes, especially with the number of tangles in
the hippocampus; (4) a distinct immunoreaction of alpha B-crystallin
in Microglia
in the substantia nigra and in the hippocampus in PDD. These results
indicate that astrocytes react to the disease conditions in AD and
in PDD in a similar way, namely by the increased expression of small
heat shock proteins, and present additional evidence for the thesis
that the pathology of the dementia in PD is related to that in AD
Torreilles F, Salman-Tabcheh S, Guerin M, Torreilles J (1999)
Neurodegenerative disorders: the role of peroxynitrite. Brain
Res.Brain Res.Rev. 30:153-163
Abstract: Inflammatory reaction is
thought to be an important contributor to neuronal damage in
neurodegenerative disorders such as Alzheimer's disease (AD),
Parkinson's disease (PD),
multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and the
Parkinsonism dementia
complex of Guam. Among the toxic agents released in brain tissues by
activated cells, we focus attention in this review on peroxynitrite,
the product of the reaction between nitric oxide (NO) and
superoxide. Peroxynitrite is a strong oxidizing and nitrating agent
which can react with all classes of biomolecules. In the CNS it can
be generated by Microglial
cells activated by pro-inflammatory cytokines or beta-amyloid
peptide (beta-A) and by neurons in three different situations:
hyperactivity of glutamate neurotransmission, mitochondrial
dysfunction and depletion of L-arginine or tetrahydrobiopterin. The
first two situations correspond to cellular responses to an initial
neuronal injury and the peroxynitrite formed only exacerbates the
inflammatory process, whereas in the third situation the
peroxynitrite generated directly contributes to the initiation of
the neurodegenerative process
Willing AE, Sudberry JJ, Othberg AI, Saporta S, Poulos SG,
Cameron DF, Freeman TB, Sanberg PR (1999) Sertoli cells decrease
Microglial
response and increase engraftment of human hNT neurons in the
hemiParkinsonian rat
striatum. Brain Res.Bull. 48:441-444
Abstract: Sertoli cells
(SCs) provide immune protection and nutritive support to the
developing germ cells in the testis. Sertoli cells have also been
shown to provide immune protection to islets transplanted outside
the testes. In this study, the ability of these cells to diminish
the infiltration/activation of Microglia
into a neural graft implanted in the lesioned striatum of a
hemiParkinsonian rat was
investigated. Human neuron-like cells (hNT neurons) were implanted
either alone or in combination with rat SCs. Three months later, the
animals were sacrificed and immunohistochemistry was performed to
determine the survival of the xenografted neurons as well as
Microglial
infiltration/activation. Cotransplantation of the SCs with the hNT
neurons increased graft survival and was associated with an increase
in graft size. Furthermore, there were fewer Microglia
present in the grafted tissue of the cotransplantation groups. These
results show that SCs retain their immunosuppressive ability even
within the brain. As immune responses to grafted neural tissue
within the central nervous system become better understood, this
ability of the SCs to provide localized immunosuppression to the
transplanted tissue may become more important. This is particularly
true as the search for alternative sources of neural tissue to treat
neurodegenerative diseases expands to encompass other species
Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but
absence of apoptotic nigral neurons in long-standing Parkinson's
disease. Mov Disord. 13:221-227
Abstract: The cause and mechanism
of neuronal cell death in the substantia nigra of patients with
Parkinson's disease (PD)
are unknown. There is also controversy about whether the cell death
results from a single event followed by cell loss consistent with
aging or whether there is an ongoing pathologic process. Using
postmortem tissue obtained from the Parkinson's
Disease Society Brain Tissue Bank in London, we have sought to
establish whether apoptosis, or more specifically DNA fragmentation
of neurons, is a prominent feature of nigral pathology. In addition,
we have studied Microglial
activation in the substantia nigra as an indicator of ongoing
pathology using the highly sensitive markers CR3/43 and EBM11.
Reactive astrocytes have been assessed using immunostaining for
glial fibrillary acidic protein (GFAP). Ten patients with
pathologically proven PD were studied. In all cases, regardless of
disease duration, severity, drug treatment, or age of the patient,
there was no evidence of apoptosis in the substantia nigra as
assessed by in situ end-labeling of DNA fragments using biotinylated
dUTP and terminal deoxynucleotidyl transferase (TdT). In contrast, a
case of multiple system atrophy (MSA) served as a positive control
for the technique. In this case, positive DNA end-labeling could be
found in neurons and non-neuronal cells in the brain stem. In the PD
cases, there was, however, localized pathology in the substantia
nigra as revealed by the CR3/ 43 and EBM11 markers for activated
Microglia.
This process seemed independent of disease duration and was florid
even in patients with severe neuronal loss. It remains to be
determined to what extent the activation of glial cells reflects
progressive nigral pathology, and whether those factors which are
classically associated with prominent apoptotic neuronal cell death
in vivo, such as neurotrophic factor deprivation, are prime causes
of nigral neuronal loss in PD. Future studies should focus on
recent-onset PD or incidental Lewy body disease to further address
these questions
Borlongan CV, Saporta S, Sanberg PR (1998) Intrastriatal
transplantation of rat adrenal chromaffin cells seeded on
microcarrier beads promote long-term functional recovery in
hemiParkinsonian rats.
Exp.Neurol. 151:203-214
Abstract: Possible biologic treatments
for Parkinson's disease, a
disorder caused by the deterioration of dopaminergic neurons
bridging the nigrostriatal system, have recently focused on fetal
cell transplantation. Because of ethical and tissue availability
issues concerning fetal cell transplantation, alternative cell
sources are being developed. The adrenal medulla has been used as a
cell transplant source because of the capacity of the cells to
provide catecholamines and to transform into a neuronal phenotype.
However, adrenal tissue transplants have shown limited success,
primarily because of their lack of long-term viability. Recently,
seeding adrenal chromaffin cells on microcarrier beads has been
shown to enhance the cell viability following neural
transplantation. In the present study, we further investigated
whether transplantation of rat adrenal chromaffin cells seeded on
microcarrier beads into the striatum of 6-hydroxydopamine-induced
hemiParkinsonian rats would
result in a sustained functional recovery. Behavioral tests using
the apomorphine-induced rotational and elevated body swing tests up
to 12 months posttransplantation revealed a significant behavioral
recovery in animals that received adrenal chromaffin cells seeded on
microcarrier beads compared to animals that received adrenal
chromaffin cells alone, medium alone, or beads alone. Histological
examination of tissue at 14 months posttransplantation revealed
evidence of tyrosine hydroxylase-positive cells and an on-going
glial response in animals transplanted with adrenal chromaffin cells
seeded on microcarrier beads, in contrast to absence of such
immunoreactive responses in the other groups. These findings support
a facilitator role for microcarrier beads in transplantation of
adrenal chromaffin cells or other cells that are easily rejected by
the CNS
Chen S, Le WD, Xie WJ, Alexianu ME, Engelhardt JI, Siklos L,
Appel SH (1998) Experimental destruction of substantia nigra
initiated by Parkinson
disease immunoglobulins. Arch.Neurol. 55:1075-1080
Abstract:
BACKGROUND: Increased levels of free radicals and oxidative stress
may contribute to the pathogenesis of substantia nigra (SN) injury
in Parkinson disease (PD),
but the initiating etiologic factors remain undefined in most cases.
OBJECTIVE: To determine the potential importance of immune
mechanisms in triggering or amplifying neuronal injury, we assayed
serum samples from patients with PD to determine the ability of IgG
to initiate relatively specific SN injury in vivo. METHODS: IgG
purified from the serum of 5 patients with PD and 10 disease control
(DC) patients was injected into the right side of the SN in adult
rats. Coronal sections were cut from the whole brain at the level of
the stereotaxic injections, stained for tyrosine hydroxylase and
with cresyl violet, and cellular profiles were counted in identical
brain regions at the injection and contralateral sides. The ratio of
cell profile counts of the corresponding injected and uninjected
regions was used as an internal standard. RESULTS: Four weeks
following injection of IgG, a 50% decrease in tyrosine
hydroxylase-positive cellular profiles was noted on the injected
sides compared with the contralateral sides of the same animals.
Similarly, applied DC IgG caused only an 18% decrease. Cresyl violet
staining revealed a 35% decrease in neuronal profiles of PD IgG
injected into the SN pars compacta compared with the contralateral
uninjected side, whereas DC IgG caused a minimal 10% decrease. Even
at 4 weeks after the PD IgG injections, perivascular inflammation
and significant Microglial
infiltration were present near injured SN pars compacta neurons. No
cytotoxic effects of PD IgG were noted in choline
acetyltransferase-positive neurons after stereotaxic injections into
the medial septal region. Absorption of PD IgG with mesencephalic
membranes and protein A agarose gel beads removed cytotoxicity,
while absorption with liver membranes did not change the
cytotoxicity. CONCLUSIONS: Our data suggest that PD IgG can initiate
a relatively specific inflammatory destruction of SN pars compacta
neurons in vivo and demonstrate the potential relevance of immune
mechanisms in PD
Kohutnicka M, Lewandowska E, Kurkowska-Jastrzebska I,
Czlonkowski A, Czlonkowska A (1998) Microglial
and astrocytic involvement in a murine model of Parkinson's
disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP). Immunopharmacology 39:167-180
Abstract: We have studied
the reaction of glial cells in mice treated with an intraperitoneal
administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP), a selective neurotoxin of dopaminergic nigrostriatal
neurons. Signs of injury to the dopaminergic neurons started on the
1st day after MPTP administration and progressed up to the end of
the observation time (21st day). A transient Microglial
reaction was demonstrated from the 1st until the 14th day in the
substantia nigra (SN) and striatum. The cells showed an increase in
number and changes in morphology. At the ultrastructural level,
signs of phagocytosis and features indicating the secretion of
biologically active substances were observed. Astrocytosis followed
the Microglial
reaction by one day and was noticed until the end of the observation
time. Interleukin-6 immunoreactivity was observed within Microglia
and astrocytes in the SN on days 2 and 3. There were no signs of
depletion of dopaminergic cells or glial activation after the
administration of MPTP simultaneously with pargyline, an inhibitor
of monoamine oxidase-B that prevents MPTP neurotoxicity. Our study
indicates that Microglia
and astrocytes are involved in the pathological process in the
nigrostriatal system following MPTP administration. MPTP alone is
not responsible for glial cell activation but its metabolite MPP+
and/or agents released by injured neurons may participate in this
process
McGeer EG, McGeer PL (1998) The importance of inflammatory
mechanisms in Alzheimer disease. Exp.Gerontol. 33:371-378
Abstract:
Lesions in such chronic neurodegenerative disorders as Alzheimer
disease (AD), Parkinson
disease, the Parkinsonism
dementia complex of Guam, and amyotrophic lateral sclerosis have
associated with them a variety of proteins known to be involved in
inflammatory processes. This is particularly true of AD, where
inflammatory reactions are thought to be important contributors to
the neuronal loss. Proteins present include complement proteins,
complement inhibitors, acute phase reactants, inflammatory
cytokines, proteases, and protease inhibitors. Studies of cultured
human astrocytes and Microglia,
obtained from postmortem brain, have established that nearly all of
these proteins are produced by one or another of these cell types.
Human neurons also produce many inflammatory proteins and their
inhibitors, creating complex interactions. Accumulations of amyloid
and extracellular tangles apparently act as irritants, causing the
activation of complement, the initiation of reactive changes in
Microglia,
and the release of potentially neurotoxic products. Such products
include the membrane attack complex, oxygen free radicals, and
excess glutamate. Twenty epidemiological studies that have been
published to date indicate that populations taking antiinflammatory
drugs have a significantly reduced prevalence of AD or a slower
mental decline. One small clinical trial with indomethacin showed
arrest of the disease over a six-month period. Therapeutic
intervention in key inflammatory processes holds great promise for
the amelioration of AD and possibly other neurodegenerative
disorders
McGeer PL, McGeer EG (1998) Mechanisms of cell death in
Alzheimer disease--immunopathology. J.Neural Transm.Suppl
54:159-166
Abstract: Lesions in such chronic neurodegenerative
disorders as Alzheimer disease, Parkinson
disease, the Parkinsonism
dementia complex of Guam and amyotrophic lateral sclerosis have
associated with them a variety of proteins known to be involved in
inflammatory processes. This is particularly true of Alzheimer
disease where inflammatory reactions are thought to be important
contributors to the neuronal loss. They include complement proteins,
complement inhibitors, acute phase reactants, inflammatory
cytokines, proteases and protease inhibitors. Studies of cultured
human astrocytes and Microglia,
obtained from postmortem brain, have established that nearly all of
these proteins are produced by one or another of these cell types.
Human neurons also produce many inflammatory proteins and their
inhibitors, creating complex interactions. Accumulations of amyloid
and extracellular tangles apparently act as irritants, causing the
activation of complement, the initiation of reactive changes in
Microglia,
and the release of potentially neurotoxic products. Such products
include the membrane attack complex, oxygen free radicals and excess
glutamate. Twenty epidemiological studies that have been published
to data indicate that populations taking antiinflammatory drugs have
a significantly reduced prevalence of Alzheimer disease or a slower
mental decline. One small clinical trial with indomethacin showed
arrest of the disease over a 6 month period. Therapeutic
intervention in key inflammatory processes holds great promise for
the amelioration of Alzheimer disease and possibly other
neurodegenerative disorders
McGeer PL, McGeer EG (1998) Glial cell reactions in
neurodegenerative diseases: pathophysiology and therapeutic
interventions. Alzheimer Dis.Assoc.Disord. 12 Suppl
2:S1-S6
Abstract: A variety of proteins known to be involved in
inflammatory processes are associated with lesions in chronic
neurodegenerative disorders such as Alzheimer disease (AD),
Parkinson's disease (PD),
and amyotrophic lateral sclerosis (ALS). This is particularly true
of AD, in which inflammatory reactions are believed to be important
contributors to the neuronal loss. Inflammatory proteins associated
with AD include complement proteins, complement inhibitors,
acute-phase reactants, inflammatory cytokines, proteases, and
protease inhibitors. Studies of cultured human astrocytes and
Microglia
obtained from postmortem brain have established that almost all of
these proteins are produced by one or the other of these two cell
types. Human neurons also produce many inflammatory proteins and
their inhibitors, creating complex interactions. Accumulations of
amyloid, extracellular tangles, or Lewy bodies apparently act as
irritants, causing the activation of complement, the initiation of
reactive changes in Microglia,
and the release of potentially neurotoxic products such as the
membrane attack complex, oxygen free radicals, and excess glutamate.
A number of epidemiologic studies indicate that populations taking
anti-inflammatory drugs have a sharply reduced prevalence of AD. One
small clinical trial with indomethacin showed arrest of the disease
over a 6-month period. Therapeutic intervention in key inflammatory
processes holds great promise for the amelioration of AD and
possibly other neurodegenerative disorders
Nakajima K, Kohsaka S (1998) [Microglia: function in the pathological state]. No To Shinkei 50:5-16
Schwarz SC, Schwarz J, Sautter J, Oertel WH (1998) Effects of
macrophage migration inhibitory factor and macrophage migration
stimulatory factor on function and survival of foetal dopaminergic
grafts in the 6-hydroxydopamine rat model of Parkinson's
disease. Exp.Brain Res. 120:95-103
Abstract: Activated Microglia
play an important role in the rejection of intracerebral grafts and
the degeneration of axotomized neurones. We studied the effect of
macrophage migration stimulatory factor (MSF) or macrophage
migration inhibitory factor (MIF) on allogeneic foetal mesencephalic
dopaminergic grafts transplanted into the striatum of
6-hydroxydopamine-lesioned rats. Rotation testing revealed a
significant compensation of lesion-induced motor asymmetry 3 weeks
post-grafting in animals treated with MIF and vehicle-treated
controls compared with pre-graft values (Student's t-test, P < or
= 0.005) and MSF-treated animals (ANOVA, post hoc Fisher PLSD test,
P < or = 0.05). The MSF group showed no significant compensation.
Graft recipients with MIF application (1452.06 +/- 164.32 tyrosine
hydroxylase-positive ventral mesencephalic cells) and controls
(1753.21 +/- 165.51 tyrosine hydroxylase-positive neurones)
displayed good graft survival. Animals with MSF application showed a
significant reduction of tyrosine hydroxylase-positive grafted cells
(MSF 570.36 +/- 209.49 cells) and graft volumes compared with the
MIF and the control group (ANOVA, post hoc Fisher PLSD test, P <
or = 0.05). The proportional area of Microglia
was significantly reduced in MIF animals compared with control
animals (ANOVA, post hoc Fisher PLSD test, P < or = 0.001).
Activated Microglia
and macrophages were reduced by half in the MIF-treated group
compared with MSF animals and controls. We conclude that
intrastriatal injections of MSF result in impaired function and
survival of allogeneic ventral mesencephalon (VM) grafts 3 weeks
after transplantation. MIF can reduce the number of Microglia
and macrophages in allogeneic foetal VM grafts. A reduction of
Microglia
via MIF application did not enhance graft function and survival
Schwarz SC, Seufferlein T, Liptay S, Schmid RM, Kasischke K,
Foster OJ, Daniel S, Schwarz J (1998) Microglial
activation in multiple system atrophy: a potential role for
NF-kappaB/rel proteins. Neuroreport 9:3029-3032
Abstract:
Microglial
activation is a prominent feature of affected brain areas in
multiple system atrophy. Microglia
express proinflammatory peptides, which may be a result of
activation of nuclear factor-KB. We investigated the nuclear
presence of RelA, the 65 kDa subunit of the NF-KB/RelA family in
striatum and brain stem of patients with multiple system atrophy.
Affected brain areas of patients with multiple system atrophy showed
a marked immunoreactivity for nuclear Rel A p65, which was almost
exclusively localized in activated Microglia.
Interestingly nuclear translocation of Rel A was not detected in
striatal tissue of controls and Parkinson
disease patients. Thus, NF-kappaB/Rel A complexes may play a role in
mediating Microglial
activation in multiple system atrophy
Walker DG, Beach TG, Xu R, Lile J, Beck KD, McGeer EG, McGeer
PL (1998) Expression of the proto-oncogene Ret, a component of the
GDNF receptor complex, persists in human substantia nigra neurons in
Parkinson's disease. Brain
Res. 792:207-217
Abstract: The proto-oncogene Ret, a
membrane-associated receptor protein tyrosine kinase, has recently
been shown to be a component of the glial cell line-derived
neurotrophic factor (GDNF) receptor complex. GDNF has potent
dopaminergic neurotrophic properties and has been suggested as a
treatment for Parkinson's
disease (PD). In this study, tissue sections of human substantia
nigra (SN) from normal and PD cases were examined to determine the
pattern of Ret expression in this region, and whether there was
continued Ret expression in surviving dopaminergic neurons in PD
cases. Using a polyclonal antibody to the amino terminal of Ret,
immunoreactivity was localized in the SN to dopaminergic neurons.
The antibody predominantly identified punctate deposits within
cells. A similar pattern of immunoreactivity was observed in rat and
monkey SN neurons. In neurologically normal cases, immunoreactivity
was detected in many of the SN neurons. In all the PD cases studied,
continued expression of Ret was observed in many of the surviving
dopaminergic neurons. In certain cases, it was also detected on
cells with the morphology of Microglia.
Ret expression by Microglia
was confirmed by immunoblot analysis on the human THP-1 macrophage
type cell line. However, these cells did not express the mRNA for
GDNFRalpha, the other component of the GDNF receptor complex
Bertrand E, Lechowicz W, Szpak GM, Dymecki J (1997)
Qualitative and quantitative analysis of locus coeruleus neurons in
Parkinson's disease. Folia
Neuropathol. 35:80-86
Abstract: The analysis of qualitative
changes in the locus coeruleus (LC) was performed on brains from 21
cases of Parkinson's
disease. Eleven cases were selected for quantitative analysis of the
loss of LC noradrenergic pigmented neurons. The qualitative studies
revealed uneven dissemination of the noradrenergic cells loss of
overall structure of the LC. Few preserved neurons showed
degenerative changes. Extracellular neuromelanine granules, traces
of dying neurons, were also observed. A weak astro- and Microglia
proliferation corresponded with neuronal loss. Lewy bodies were
found in the LC in all cases. The quantitative analysis revealed
that the average loss of adrenergic neurons in the LC accounts for
about 70% in relation to the control group. The degenerative changes
were observed in the whole LC, but they were most intensive in its
caudal and next in the middle segment. The results suggest also that
the degenerative process began in the middle segment and then it
spread towards caudal segment of the LC as the stages of disease
advanced
Deacon T, Schumacher J, Dinsmore J, Thomas C, Palmer P, Kott
S, Edge A, Penney D, Kassissieh S, Dempsey P, Isacson O (1997)
Histological evidence of fetal pig neural cell survival after
transplantation into a patient with Parkinson's
disease. Nat.Med. 3:350-353
Abstract: The movement disorder in
Parkinson's disease results
from the selective degeneration of a small group of dopaminergic
neurons in the substantia nigra pars compacta region of the brain. A
number of exploratory studies using human fetal tissue allografts
have suggested that transplantation of dopaminergic neurons may
become an effective treatment for patients with Parkinson's
disease and the difficulty in obtaining human fetal tissue has
generated interest in finding corresponding non-human donor cells.
Here we report a post-mortem histological analysis of fetal pig
neural cells that were placed unilaterally into the caudate-putamen
brain region of a patient suffering from Parkinson's
disease. Long-term (over seven months) graft survival was found and
the presence of pig dopaminergic neurons and other pig neural and
glial cells is documented. Pig neurons extended axons from the graft
sites into the host brain. Furthermore, other graft derived cells
were observed several millimeters from the implantation sites.
Markers for human Microglia
and T-cells showed only low reactivity in direct proximity to the
grafts. This is the first documentation of neural xenograft survival
in the human brain and of appropriate growth of non-human
dopaminergic neurons for a potential therapeutic response in
Parkinson's disease
Kawaguchi N, Yamada T, Yoshiyama Y (1997) [Expression of
interferon-alpha mRNA in human brain tissues]. No To Shinkei
49:69-73
Abstract: The localization of mRNA of interferon-alpha
(IFNA21) was examined in human brain tissues from neurologically
normal, Parkinson's and
Alzheimer's disease (AD) cases, using an in situ hybridization
method. In all cases, signals for the mRNA of IFNA21 were detected
in the white matter Microglial
cells. In AD brains, a few neurons in the parietal lobe were
intensely labeled. These results suggest that one type of IFN-alpha
protein is constitutively expressed in white matter Microglial
cells, and that expression of IFN-alpha in neuronal cells may play
some role in AD pathology
Kordower JH, Styren S, Clarke M, DeKosky ST, Olanow CW,
Freeman TB (1997) Fetal grafting for Parkinson's
disease: expression of immune markers in two patients with
functional fetal nigral implants. Cell Transplant.
6:213-219
Abstract: In a number of centers throughout the world,
fetal nigral transplantation is being performed for the treatment of
Parkinson's disease (PD).
Clinical results have been inconsistent. One parameter that differs
among transplant studies is the degree and manner by which patients
are immunosuppressed following transplantation. Indeed, the role of
the immune system following fetal grafting in humans is not well
understood. Recently, two patients from our open label trial that
received fetal nigral implants have come to autopsy. These patients
were immunosuppressed with cyclosporin for 6 mo posttransplantation
and survived for a total of 18 mo postgrafting. Robust survival of
grafted dopamine-containing cells was observed in both cases.
Immunostaining for HLA-DR revealed a dense collection of cells
within grafts from both cases. HLA-DR staining was rarely observed
within the host including nongrafted regions of the striatum. A more
detailed analysis of immune markers was performed in Case 2.
Numerous pan macrophages, T-cells, and B-cells were observed within
graft sites located in the postcommissural putamen. In contrast,
staining for these immune cells was not observed within the
ungrafted anterior putamen. These findings suggest that even in
healthy appearing functional nigral implants, grafts are invaded by
host immune cells that could compromise their long-term viability
and function. Alternatively, immune cells are known to secrete
trophic factors, which may ultimately favor graft survival and
function. Further work is needed to understand the role of the
immune system in fetal grafting
Kosel S, Egensperger R, von Eitzen U, Mehraein P, Graeber MB
(1997) On the question of apoptosis in the Parkinsonian
substantia nigra. Acta Neuropathol.(Berl) 93:105-108
Abstract:
Apoptosis has been postulated as a mechanism of nerve cell death in
Parkinson's disease. In the
present study, the substantia nigra of 22 neuropathologically
confirmed Parkinson cases
and 8 control brains was studied using the in situ end-labeling
(TUNEL) method. About 50% of Parkinsonian
brains showed a small number of TUNEL-positive glial cells in the
substantia nigra, whereas no neurons showed convincing TUNEL
positivity or any morphological signs of apoptosis. No correlation
was observed between the number of TUNEL-positive glial cells and
Microglial
activation. Our results fail to demonstrate apoptosis as a mechanism
of cell death in Parkinson's
disease
McGeer EG, McGeer PL (1997) The role of the immune system in neurodegenerative disorders. Mov Disord. 12:855-858
McGeer PL, Schwab C, McGeer EG, Haddock RL, Steele JC (1997)
Familial nature and continuing morbidity of the amyotrophic lateral
sclerosis-Parkinsonism
dementia complex of Guam. Neurology 49:400-409
Abstract:
Chamorros suffer from two neurologic syndromes known as ALS and the
Parkinsonism-dementia
complex (PDC) of Guam. We report mortality figures for these
syndromes during 1991 to 1995 and compare them with those at 5-year
intervals dating back to 1951. In contrast to predictions of disease
disappearance, both syndromes remain prevalent. However, age of
onset and age at death have increased for both syndromes, suggesting
that shifting environmental factors are causing disease
postponement. We also report the clinical, familial,
neuropathologic, and immunohistochemical findings on a consecutive
autopsy series of Guamanian Chamorro cases. Twelve cases were
diagnosed as PDC, known locally as "bodig," and three as
ALS, known locally as "lytico." All but three of these
fifteen patients had a pronounced family history of similar illness.
Eight of twelve boding patients had siblings who were also affected
with bodig; two of three lytico cases had siblings afflicted with
lytico. The family histories are compatible with genetic
transmission of each syndrome. The neuropathology of bodig is
characterized by severe and widespread neurofibrillary tangle (NFT)
development. NFTs are surrounded by reactive Microglia
and reactive astrocytes, and complement proteins and other molecules
connected with inflammation are associated with them. Similar
inflammatory responses also occur in Alzheimer's disease (AD) but
have been largely attributed to the presence of senile plaques.
These data indicate that tangles, as well as plaques, generate
inflammatory reactions that such reactions may exacerbate the
fundamental pathology in bodig as well as in AD
Pearce RK, Owen A, Daniel S, Jenner P, Marsden CD (1997)
Alterations in the distribution of glutathione in the substantia
nigra in Parkinson's
disease. J.Neural Transm. 104:661-677
Abstract: Depletion of
reduced glutathione occurs in the substantia nigra in Parkinson's
disease and in incidental Lewy body disease (presymptomatic
Parkinson's disease) which
may implicate oxidative stress in the neurodegenerative process. In
this study mercury orange fluorescent staining and immunostaining
with an antibody to reduced glutathione have been used to determine
the distribution of reduced glutathione in the substantia nigra in
Parkinson's disease
compared with normal individuals. Mercury orange staining showed
moderate background levels of fluorescence in the neuropil in both
control and Parkinson's
disease substantia nigra and localised reduced glutathione to the
somata of melanized nigral neurons and glial elements of the
neuropil. Neuronal nuclei revealed a relative lack of fluorescence
after mercury orange staining. There was a significant depletion of
reduced glutathione in surviving neurons in Parkinson's
disease compared to nerve cell populations in control tissue.
Mercury orange fluorescence indicated a high concentration of
reduced glutathione in a subpopulation of non-neuronal cells, most
likely astrocytes or Microglia.
Immunohistochemical examination of nigral tissue from the same
Parkinson's disease and
control patients with an antibody to glutathione showed staining in
neuronal perikarya and axonodendritic processes of melanized nigral
neurons which was generally most intense in control neurons.
Moderately intense staining of the background neuropil, most
prominent in control nigras, and staining of capillary walls was
also detected. Intense staining was seen in cells with the
morphological features of glial cells in both control and PD nigra.
These data show a significant presence of reduced glutathione in the
cell bodies and axons of nigral neurons. They are in agreement with
biochemical studies showing depletion of reduced glutathione in
substantia nigra in Parkinson's
disease, and indicate a significant loss of neuronal reduced
glutathione in surviving nigral neurons in Parkinson's
disease
Pratt BM, McPherson JM (1997) TGF-beta in the central nervous
system: potential roles in ischemic injury and neurodegenerative
diseases. Cytokine Growth Factor Rev. 8:267-292
Abstract: The
Transforming Growth Factor-betas (TGF-beta) are a group of
multifunctional proteins whose cellular sites of production and
action are widely distributed throughout the body, including the
central nervous system (CNS). Within the CNS, various isoforms of
TGF-beta are produced by both glial and neural cells. When evaluated
in either cell culture or in vivo models, the various isoforms of
TGF-beta have been shown to have potent effects on the
proliferation, function, or survival of both neurons and all three
glial cell types, astrocytes, Microglia
and oligodendrocytes. TGF-beta has also been shown to play a role in
several forms of acute CNS pathology including ischemia,
excitotoxicity and several forms of neurodegenerative diseases
including multiple sclerosis, Parkinson's
disease, AIDS dementia and Alzheimer's disease
Ruberg M, Brugg B, Prigent A, Hirsch E, Brice A, Agid Y
(1997) Is differential regulation of mitochondrial transcripts in
Parkinson's disease related
to apoptosis? J.Neurochem. 68:2098-2110
Abstract: A cDNA library
of substantia nigra pars compacta from a patient with Parkinson's
disease (PD) was differentially screened with probes of normal and
Parkinsonian substantia
nigra enriched in neuronal transcripts. Fifty-eight clones were
isolated; 39 were subunits of mitochondrial respiratory complexes I
and IV. Parallel screening of a cDNA library derived from normal
substantia nigra confirmed differential representation of the
transcripts in the substantia nigra pars compacta. In situ
hybridization in postmortem brain from Parkinsonian
and control subjects, with representative complex I and complex IV
probes, showed increased labeling, at the cellular level, of the
complex I subunit ND1 in neurons of the lateral substantia nigra,
where cell death is greatest in PD, but decreased labeling in the
medial substantia nigra where fewer cells die. Expression of a
complex IV subunit, COXI, increased, however, in both parts of the
structure. Increased expression of ND1 and COXI was also observed in
nerve growth factor-differentiated PC12 cells undergoing apoptosis
induced by tumor necrosis factor-alpha, suggesting that the
differential regulation of certain mitochondrial mRNAs may be
associated with this form of cell death. This in vitro model of
apoptosis is potentially relevant to the death of dopaminergic
neurons in PD, because these cells express the tumor necrosis
factor-alpha receptor, and neighboring Microglial
cells in patients synthesize the cytokine
Ruberg M, France-Lanord V, Brugg B, Lambeng N, Michel PP,
Anglade P, Hunot S, Damier P, Faucheux B, Hirsch E, Agid Y (1997)
[Neuronal death caused by apoptosis in Parkinson
disease]. Rev.Neurol.(Paris) 153:499-508
Abstract: The identity
of the neuronal populations (dopaminergic, noradrenergic,
serotoninergic, cholinergic) that die in Parkinson's
disease is well established. The cause of this degeneration, and the
mechanism by which it takes place is still unknown, although there
is data, at least for the dopaminergic neurons, suggesting that
oxidative stress might play a role. In addition, recent
ultrastructural studies of dopaminergic neurons in patients with
Parkinson's disease have
shown that these neurons die by apoptosis, and immunocytochemical
studies have shown that the cytokine TNF-alpha, observed in
Microglial
cells in the substantia nigra of patients post-mortem, might play a
role, as might the transcription factor NF-kappa B, which is
translocated into the nucleus of dopaminergic neurons in patients, a
sign of its activation. We have developed an in vitro model of
dopaminergic cell death that accounts for these observations. In
both differentiated PC12 cells and primary cultures of mesencephalic
neurons, we have shown that when the sphingomyelin-dependent
signaling pathway is activated, these cells die by apoptosis,
preceded by the production of superoxide radicals in the
mitochondria and the nuclear translocation of NF-kappa B. TNF-alpha
is known to induce all three such events: apoptosis, activation of
the sphingomyelin pathway, free radical production. Our results
suggest that the superoxide radicals are used as signalling
molecules within the sphingomyelin pathway. These observations may
help to explain the origin of the evidence, in postmortem brain from
Parkinsonian patients, for
oxidative stress, hypothesized to be an etiological factor in this
disease
Tanaka M (1997) [Oxidative stress and the brain]. Nippon
Ronen Igakkai Zasshi 34:706-710
Abstract: Although the cause of
Parkinson's disease is
unknown, oxidative stress has been implicated in its pathogenesis.
This theory postulates that normal metabolic processes in the
nigrostriatal dopaminergic system may lead to loss of neurons, and
that iron-dependent membrane lipid peroxidation may play an
important role in the neuronal death. Recent research concerning
iron-dependent lipid peroxidation is presented. First, catechols
(including dopa and dopamine) and iron form strong oxidizing
complexes and induce lipid peroxidation (LPO) in phospholipid
liposomes. Active oxygen species including superoxide, hydrogen
peroxide, hydroxyl radical and singlet oxygen, do not participate in
this LPO, which is inhibited by an excess of dopa (dopamine).
Cultured neurons and the substantia nigra are vulnerable to LPO.
Second, synthetic melanin prepared by the autooxidation of catechols
promotes LPO in the presence of iron. The effects of scavenging
agents indicate that this LPO is mediated by superoxide, but not by
other oxygen free radicals. Neuronal cell cultures are destroyed by
this LPO. Third, catechols and superoxide produced by Microglia
cause the release of iron from ferritin. Microglia
stimulated by phorbol myristate acetate produce superoxide and cause
the release of iron from ferritin. Catechols also induce
mobilization of ferritin iron. The released iron (i.e. loosely-bound
iron) is available to iron-dependent LPO. These data suggest that
the biochemical and morphological characteristics of the substantia
nigra, which are concomitant with its functional role, provoke
iron-dependent lipid peroxidation. It is essential to elucidate how
iron bound loosely to low molecules comes into contact with
catechols, neuromelanin and superoxide. Drugs that chelate iron
site-specifically or modulate the Microglial
function may bring about some favorable changes in the disease
process
Tompkins MM, Basgall EJ, Zamrini E, Hill WD (1997)
Apoptotic-like changes in Lewy-body-associated disorders and normal
aging in substantia nigral neurons. Am.J.Pathol.
150:119-131
Abstract: In Parkinson's
disease and other Lewy-body-associated disorders, the substantia
nigra pars compacta undergoes degeneration, but the mechanism of
cell death has not been previously described. The substantia nigra
of normal and Alzheimer's disease cases were compared with
substantia nigra from patients with Lewy-body-associated disorders
(Parkinson's disease,
concomitant Alzheimer's/Parkinson's
disease, and diffuse Lewy body disease) using in situ end labeling
to detect fragmented DNA. In situ end-labeled neurons demonstrated
changes resembling apoptosis: nuclear condensation, chromatin
fragmentation, and formation of apoptotic-like bodies.
Ultrastructural analysis confirmed nuclear condensation and
formation of apoptotic-like bodies. Apoptotic-like changes were seen
in the substantia nigra of both normal and diseased cases;
concomitant Alzheimer's/Parkinson's
disease and diffuse Lewy body disease cases had significantly higher
amounts of apoptotic-like changes than normal controls or Alzheimer
patients. The finding of neuronal death by apoptosis may have
relevance for the development of new treatment strategies for
Parkinson's disease and
related disorders
Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I,
Czlonkowski A (1996) Microglial
reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
induced Parkinson's disease
mice model. Neurodegeneration. 5:137-143
Abstract: We studied the
Microglial
reaction in mice using the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model
for Parkinson's disease
(PD). Microglial
cells were identified by means of the Griffonia simplicifolia lectin
(GSA-I-B4). Dopaminergic neurons were marked by tyrosine hydroxylase
antibodies. Microglial
activation was demonstrated by an increase in cellular number and
changes of morphology (increased lectin staining, larger cell bodies
and thicker processes) were seen in the substantia nigra from the
1st to the 14th day and in the striatum from the 1st to the 4th day
after intoxication. Depletion of dopaminergic neurons was most
pronounced 7 and 14 days following the treatment. The results
suggest that Microglial
activation may be involved in the sequence of pathological changes
that lead to dopaminergic neuronal damage after MPTP intoxication
Goto K, Mochizuki H, Imai H, Akiyama H, Mizuno Y (1996) An
immuno-histochemical study of ferritin in
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced
hemiParkinsonian monkeys.
Brain Res. 724:125-128
Abstract: Iron is increased in the
substantia nigra of patients with Parkinson's
disease, but the mechanism of its accumulation is unknown. We report
the distribution of ferritin in the basal ganglia of
hemiParkinsonian monkeys
made by MPTP. We stereotactically injected MPTP unilaterally into
the caudate nucleus of four monkeys, and the substantia nigra and
the basal ganglia regions were stained for L-ferritin by an
immunohistochemical method. The ferritin immuno-staining was most
intense in the pallidum and the pars reticulata of the substantia
nigra on both injected and non-injected sides. No significant
difference was noted in the immunostaining for ferritin in the pars
compacta of the substantia nigra between the injected and the
non-injected side. Iron was increased in the pars compacta of the
substantia nigra of this hemiParkinsonian
monkeys in our previous study. Normal ferritin immunostaining on the
injected side would indicate that iron accumulation is not related
to altered metabolism of L-ferritin in this model
Sanberg PR, Borlongan CV, Saporta S, Cameron DF (1996)
Testis-derived Sertoli cells survive and provide localized
immunoprotection for xenografts in rat brain. Nat.Biotechnol.
14:1692-1695
Abstract: Transplantation of neural tissue into the
mammalian central nervous system has become an alternative treatment
for neurodegenerative disorders such as Parkinson's
disease. Logistical and ethical problems in the clinical use of
human fetal neural grafts as a source of dopamine for Parkinson's
disease patients has hastened a search for successful ways to use
animal dopaminergic cells for human transplantation. The present
study demonstrates that transplanted testis-derived Sertoli cells
into adult rat brains survive. Furthermore, when cotransplanted with
bovine adrenal chromaffin cells (xenograft), Sertoli cells produce
localized immunoprotection, suppress Microglial
response and allow the bovine cells to survive in the rat brain
without continuous systemic immunosuppressive drugs. These novel
features support Sertoli cells as a viable graft source for
facilitating the use of xenotransplantation for Parkinson's
disease and suggest their use as facilitators, (i.e., localized
immunosuppression) for cell transplantation in general
Schwab C, Steele JC, McGeer PL (1996) Neurofibrillary tangles
of Guam Parkinson-dementia
are associated with reactive Microglia
and complement proteins. Brain Res. 707:196-205
Abstract:
Guamanian Parkinsonism-dementia,
locally described as bodig, is characterized by the widespread
appearance of neurofibrillary tangles in cortical and subcortical
areas. These tangles have similar regional distribution and
immunohistochemical profile to those found in Alzheimer disease
(AD). We studied the immunohistochemical staining of these tangles,
as well as those of AD, using antibodies to complement proteins and
related molecules. In bodig, as in AD, extracellular tangles were
intensely decorated with antibodies to C1q, C4d and C3d, but not
fraction Bb of factor B, properidin or immunoglobulins. This is
evidence that the classical, but not the alternative complement
pathway is activated on extracellular tangles and that the
activation is independent of antibodies. Immunohistochemical
staining for amyloid P, an in vitro activator of complement, was
remarkably similar to that for the C1q, C4d and C3d in both bodig
and AD. This was not the case for beta-amyloid protein (BAP),
another in vitro complement activator. Positive staining was
observed in only a minority of extracellular tangles in bodig and
was only rarely observed in those of AD. BAP would therefore not
appear to be a candidate for activating complement on extracellular
neurofibrillary tangles. Reactive Microglia
and reactive astrocytes were closely associated with complement
positive extracellular neurofibrillary tangles, indicating an
inflammatory response similar to that seen in AD
Schwarz J, Weis S, Kraft E, Tatsch K, Bandmann O, Mehraein P,
Vogl T, Oertel WH (1996) Signal changes on MRI and increases in
reactive microgliosis, astrogliosis, and iron in the putamen of two
patients with multiple system atrophy. J.Neurol.Neurosurg.Psychiatry
60:98-101
Abstract: A correlation of clinical, MRI, and
neuropathological data is reported in two patients with multiple
system atrophy (MSA). On MRI, patient 1 showed striatal atrophy,
reduction of T2 relaxation times within most of the putamen, and a
band of hyperintense signal changes in the lateral putamen. In
patient 2, MRI disclosed only shortening of the T2 signal in the
putamen. Immunohistochemistry showed pronounced reactive
microgliosis and astrogliosis in the affected brain regions. In
patient 1, the area with the most pronounced microgliosis and
astrogliosis most likely correlated with the area of hyperintense
signal changes on MRI. This area also contained the highest amount
of ferric iron, which was increased in the putamen of patient 1 but
not patient 2. It is unlikely that the hypointense signal changes in
the putamen are due to an increase of iron alone. Reactive
Microglial
and astroglial cells may play a part in the pathogenesis of MSA
Schwarz SC, Kupsch AR, Banati R, Oertel WH (1996) Cellular
immune reactions in brain transplantation: effects of graft pooling
and immunosuppression in the 6-hydroxydopamine rat model of
Parkinson's disease. Glia
17:103-120
Abstract: We used high immunogenic mouse and low
immunogenic rat brain transplants to investigate the effect of
pooling of tissue with immunogenetic disparity on cellular immune
reactions. Foetal xenogenic mouse striatum and allogenic rat
substantia nigra were implanted into i) the 6-hydroxydopamine
lesioned striatum of outbred female Sprague-Dawley rats as a pooled
cell suspension, or into ii) the unlesioned and lesioned striata as
non-pooled separate deposits, with or without immunosuppressive
treatment with cyclosporin A (Cy A). In control animals, iii) mouse
striatum was replaced by rat striatum, and iv) sham grafts with and
without immunosuppression. Six weeks post grafting, brains were
semiquantitatively processed using immunocytochemical markers for
Microglia,
astrocytes, T-helper cells, and macrophages, major
histocompatibility class (MHC) I and II expression. The total amount
of immunoreactivity (PA) for Microglial
cells and astrocytes was pronounced and the PA for T-helper cells
and macrophages was doubled in recipients of pooled rat and mouse
cografts compared to non-pooled deposits, indicating ongoing immune
reactions with participation of glial cells. MHC I expression was
significantly increased in pooled xeno- and allogenic cografts with
and without immunosuppression compared to allogenic controls.
Expression of MHC II was significantly increased in pooled cografts
without immunosuppression. In recipients of separate, non-pooled
heteroimmunogenic cotransplants, MHC I and II expression was
significantly increased in xenogenic deposits with and without
immunosuppression. MHC II was as well significantly increased in
allogenic deposits without immunosuppression. Immunosuppressed
animals with non-pooled allogenic mouse cografts showed low levels
of cellular immune parameters. In conclusion non-pooled
heteroimmunogenic grafts lead to less pronounced immune reactions
compared to pooled grafts and immunosuppressive treatment with Cy A
has a beneficial effect on acute transplant-associated immune
parameters
Shergill JK, Cammack R, Cooper CE, Cooper JM, Mann VM,
Schapira AH (1996) Detection of nitrosyl complexes in human
substantia nigra, in relation to Parkinson's
disease. Biochem.Biophys.Res.Commun. 228:298-305
Abstract:
Idiopathic Parkinson's
disease (PD) involves a documentable decline in the activity of
mitochondrial complex I in substantia nigra (1-3). We have EPR
spectroscopy to investigate complex I in human substantia nigra and
globus pallidus. EPR signals characteristic of the iron-sulfur
centers of complexes I and II were observed with globus pallidus,
with no significant difference between control and PD. These complex
1 signals could not be clearly observed in substantia nigra.
Instead, nitric oxide (NO.) radicals in PD nigra were detected at g
approximately 2.08, 1.98 due to [haem-NO] formation. Although an EPR
signal indicative of haem-NO was observed with control nigra, it
lacked the distinctive g approximately 1.98 trough observed with PD
nigra. As PD is associated with a reactive gliosis, the difference
in the haem-NO EPR signal, between control and PD nigra, may result
from cytotoxic NO. generated by Microglia
in PD substantia nigra
Unsicker K, Suter-Crazzalora C, Krieglstein K (1996) Growth
factor function in the development and maintenance of midbrain
dopaminergic neurons: concepts, facts and prospects for TGF-beta.
Ciba Found.Symp. 196:70-80
Abstract: Dopaminergic neurons of the
nigrostriatal system are important in the control of motor
performance and degenerate in Parkinson's
disease. Therefore, in order to design novel strategies for the
treatment of Parkinson's
disease, it is important for us to understand their development,
function, trophic factor requirements, plasticity and susceptibility
to toxic influences. A large and still increasing number of growth
factors have been implicated in the regulation of the survival and
differentiation of dopaminergic neurons. These factors may also
protect against a variety of toxic influences. On the basis of their
localization, putative sources and mechanisms of actions, such
growth factors fall into several categories: (i) local factors
within the midbrain influencing proliferation, transmitter
phenotype, migration, positioning and neurite growth of stem cells
and early neurons; (ii) factors acting retrogradely from the
striatum, which are responsible for intrastriatal sprouting and
navigation of newly arrived axons as well as life-long maintenance
of the dopaminergic nigrostriatal connection; (iii) factors coming
into play when the system is toxically impaired; (iv) factors
directly acting on dopaminergic neurons; and (v) factors provided by
cytokinestimulated astroglia, Microglia
and neurons affecting dopaminergic neurons anterogradely. This
article reviews actions of growth factors on dopaminergic neurons in
vitro and in vivo, with a focus on members of the transforming
growth factor (TGF)-beta superfamily. TGF-beta s may be particularly
relevant to dopaminergic neurons, since they are expressed in the
nigrostriatal system from early embryonic stages to adulthood and
are significantly up-regulated in response to lesions
Yoshida T, Tanaka M, Sotomatsu A, Hirai S (1995) Activated
Microglia
cause superoxide-mediated release of iron from ferritin.
Neurosci.Lett. 190:21-24
Abstract: Ferritin contains the greatest
part of the iron found in the brain, and the release of iron stores
from ferritin has an essential role in iron-dependent lipid
peroxidation. We examined the effect of cultured Microglia
on iron mobilization from ferritin. Microglia
stimulated by phorbol myristate acetate caused the release of iron
from ferritin, which was detected by monitoring iron-ferrozine
complex formation. This iron mobilization was mediated by Microglial
superoxide production, as evidenced by the significant inhibitory
effect of superoxide dismutase. The role of superoxide was also
supported by the close correspondence of cumulative Microglial
superoxide production, as demonstrated by the MCLA (Cypridina
luciferin analogue)-dependent chemiluminescence assay, to the time
course of iron release from ferritin. Iron release induced by
activated Microglia
may be partly responsible for the oxidative damage that is thought
to occur in Parkinson's
disease and other neurodegenerative disorders
Kuiper MA, Visser JJ, Bergmans PL, Scheltens P, Wolters EC
(1994) Decreased cerebrospinal fluid nitrate levels in Parkinson's
disease, Alzheimer's disease and multiple system atrophy patients.
J.Neurol.Sci. 121:46-49
Abstract: Nitric oxide (NO) is a recently
discovered endogenous mediator of vasodilatation, neurotransmission,
and macrophage cytotoxicity. NO is thought to have a function in
memory and in long-term potentiation. At high concentrations NO is
neurotoxic and may play a role in neurodegeneration. NO is formed
from L-arginine by the enzyme NO synthase (NOS), for which
tetrahydrobiopterin (BH4) is a necessary co-factor. Alzheimer's
disease (AD) and, to a lesser degree, Parkinson's
disease (PD) are thought to be associated with increased Microglial
activity, suggesting that NO production may be increased.
Alternatively, in circumstances of reduced levels of intracellular
L-arginine or BH4, NO production is diminished and neurotoxic oxygen
radicals may be produced. Since BH4 is decreased in AD and PD
brains, these diseases may be associated with decreased NO
production. We investigated these two alternatives by measuring the
NO degradation products nitrite and nitrate in cerebrospinal fluid
(CSF) of PD (n = 103), AD (n = 13), and multiple system atrophy
(MSA; n = 14) patients and controls (n = 20). We found for all
patient groups, compared with controls, significantly decreased
levels of nitrate, but not nitrite. This finding seems to indicate a
decreased NO production of the central nervous system (CNS) in these
neurodegenerative disorders
Morris CM, Edwardson JA (1994) Iron histochemistry of the
substantia nigra in Parkinson's
disease. Neurodegeneration. 3:277-282
Abstract: Raised tissue
iron levels in the substantia nigra in Parkinson's
disease (PD) suggests that altered iron homeostasis may underly the
disorder. We have therefore investigated the distribution of
non-haem iron in the normal and PD substantia nigra, using a
sensitive histochemical procedure, to assess the pathogenic
potential of this metal. In control cases non-haem iron staining was
highest in the substantia nigra zona reticulata (SNr) and associated
with the neuropil, oligodendrocytes, astrocytes and non-pigmented
neurones. The substantia nigra zona compacta (SNc) showed lower
non-haem iron staining than the SNr, with generalized impregnation
of the neuropil and occasional non-haem iron-positive
oligodendrocytes and astrocytes. The pigmented dopaminergic neurones
were unstained, often present in areas of neuropil with low iron
reactivity. In PD the SNc showed increased iron staining of the
neuropil with many iron-positive Microglial
cells associated with extracellular melanin. The remaining
dopaminergic neurones were unstained, though many of the
non-pigmented neurones of the SNr were iron-positive
Yamada T, Horisberger MA, Kawaguchi N, Moroo I, Toyoda T
(1994) Immunohistochemistry using antibodies to alpha-interferon and
its induced protein, MxA, in Alzheimer's and Parkinson's
disease brain tissues. Neurosci.Lett. 181:61-64
Abstract: The
localization of alpha-interferon (alpha-IFN) and its induced
protein, MxA, was examined in human brain tissues from
neurologically normal, Alzheimer's disease (AD) and Parkinson's
disease (PD) cases. In all cases, a few neurons in the superficial
cortical layers and Microglial
cells in the white matter were stained with the antibody to
alpha-IFN. In AD brains, white matter Microglia
were intensely labeled for alpha-IFN and reactive Microglia,
such as those on senile plaques, were strongly positive for MxA
protein. In PD, Lewy bodies in the substantia nigra were positive
for MxA, but there was no staining for alpha-IFN in that region.
These results suggest that increased expression of alpha-IFN in the
white matter Microglia
and appearance of MxA protein in reactive Microglia
contribute to Alzheimer pathology. The staining of some Lewy bodies
for MxA may be indicative of a viral infection or other unknown
factor
Youdim MB, Lavie L (1994) Selective MAO-A and B inhibitors,
radical scavengers and nitric oxide synthase inhibitors in
Parkinson's disease. Life
Sci. 55:2077-2082
Abstract: In the absence of identification of
either an endogenously or an exogenously derived dopaminergic
neurotoxin, the most valid hypothesis currently envisaged for
etiopathology of Parkinson's
disease (PD) is selective oxidative stress (OS) in substantia nigra
(SN). Although OS is not proven, a significant body of evidence from
studies on animal and Parkinsonian
brain neurochemistry supports it. This hypothesis is based on
excessive formation of reactive oxygen species (O2 and OH.) and
demise of systems involved with scavenging or preventing the
formation of such radicals from H2O2, generated as a consequence of
dopamine oxidation (autoxidation and deamination). Since MAO
(monoamine oxidase A and B are the major H2O2 generating enzymes in
the SN much attention has been paid to their selective inhibitors as
symptomatic and neuroprotective agents in PD. Attention should also
be given to radical scavengers (e.g. iron chelators, lipid
peroxidative inhibitors and Vitamin E derivatives) as therapeutic
neuroprotective agents in PD. This is considered valid since a
significant elevation of iron is known to occur selectively in SN
zone compacta and within the remaining melanized dopamine neurons of
Parkinsonian brains.
Although all the mechanism of iron induced oxygen free radical
formation is not fully known there is no doubt that it participates
with H2O2 (Fenton chemistry) to generate cytotoxic hydroxyl radical
(OH.) and induce tissue OS and neurodegeneration in
6-hydroxydopamine model of PD. The dramatic proliferation of
reactive amoeboid macrophages and Microglia
seen in SN of PD brains together with OS is highly compatible with
an inflammatory process, similar to what has been observed in
Alzheimer's disease and multiple sclerosis brains. This has led us
to examine the ability of reactive macrophages to produce oxygen
free radicals in response to nitric oxide (NO) production. The
latter radical has been implicated in the excitotoxicity of
glutaminergic neurons innervating the striatum and SN. Indeed we
have now observed that in reactive macrophages NO acts as a signal
transducer of O2 production which can synergize with dopamine
oxidation
Youdim MB, Lavie L, Riederer P (1994) Oxygen free radicals and neurodegeneration in Parkinson's disease: a role for nitric oxide. Ann.N.Y.Acad.Sci. 738:64-68
Van Gool D, De Strooper B, Van Leuven F, Triau E, Dom R
(1993) alpha 2-Macroglobulin expression in neuritic-type plaques in
patients with Alzheimer's disease. Neurobiol.Aging
14:233-237
Abstract: Because it has been suggested that alpha 2M
could be involved in the generation of amyloid peptide, attention
was given to a possible association of alpha 2M expression and
amyloid accumulation in the brain. Therefore, we investigated the
presence of the proteinase inhibitor alpha 2-macroglobulin (alpha
2M) in the cerebra of 4 patients with Alzheimer's Disease (AD). One
case of a patient with Down's syndrome, 2 cases of patients with
Dementia of the Lewy Body type (DLB), 1 case of an aged, clinically
nondemented person who displayed many amyloid plaques, and 3 normal
aged control brains were also studied. The results obtained by
immunocytochemistry with monoclonal antibodies directed against two
different epitopes of human alpha 2M showed an association of alpha
2M, only with neuritic-type plaques in patients with AD. No alpha 2M
immunoreactivity was found in either preamyloid-type plaques or
burned out-type plaques in AD, DLB, or aged nondemented controls.
The results do not support a direct role of this proteinase
inhibitor in the formation of amyloid. Because alpha 2M is observed
to be associated with reactive Microglia
in the outer border of the neuritic plaques, the data suggest that
alpha 2M could be a marker for an inflammatory cellular process in
these neuritic plaques
Youdim MB, Riederer P (1993) The role of iron in senescence
of dopaminergic neurons in Parkinson's
disease. J.Neural Transm.Suppl 40:57-67
Abstract: In Parkinson's
disease (PD) an elevation of iron with staging of the disease has
been observed in the substantia nigra (SN), especially the zona
compacta (ZC). The iron is found to be present in glia, active
Microglia,
macrophages, oligodendrocytes, outside the degenerated dopamine
neurons and as a mild halo around Lewy bodies and within melanized
dopamine neurons of SNZC. Although in control brains iron is absent
in melanized dopamine neurons, in PD it is bound to neuromelanin in
a fashion similar to the interaction of iron with synthetic
dopamine-melanin. The iron in SNZC is thought to induce oxidative
stress and thus be associated with the reported decreases of
glutathione peroxidase activity, reduced glutathione (GSH),
mitochondrial Complex I activity, calcium binding protein and
increase of basal lipid peroxidation. An animal (rat) model of PD
has been described in which intranigral iron injection induces a
relatively specific lesioning of dopamine neurons resulting in
behavioural and biochemical Parkinsonism
in rats. Support for the neurotoxicity of iron liberated from an
endogenous source has come from the 6-hydroxydopamine model of PD.
This neurotoxin is thought to owe its toxicity to the liberation of
iron from ferritin, which in turn alters the homeostasis of
mitochondrial Ca2+ with the subsequent depletion of tissue GSH,
resulting in oxidative stress. Pretreatment of rats with
intraventricular injection of a relatively selective prototype iron
chelator, desferrioxamine (desferal), attenuates the
6-hydroxydopamine lesion of nigrostriatal dopamine. Thus iron can
fulfill the role of a neurotoxin. However it remains to be
established whether its role in PD is primary or secondary to some
other neurotoxic event
Kida E, Barcikowska M, Niemczewska M (1992)
Immunohistochemical study of a case with progressive supranuclear
palsy without ophthalmoplegia. Acta Neuropathol.(Berl)
83:328-332
Abstract: A case of progressive supranuclear palsy
(Steele-Richardson-Olszewski syndrome; PSP) with Parkinsonism
and absence of gaze palsy or mental changes is reported.
Neuropathological examination, apart from typical changes, showed,
lack of midbrain tegmentum demyelination, marked loss of Purkinje
cells and presence of hyalin-like bodies in individual neurons of
the substantia nigra. Immunostaining against tau-1 protein revealed
the prevalence of a diffuse reaction in locus coeruleus neurons;
reflecting either different ability of these cells to accumulate
straight filaments, or a various time sequence of neurofibrillary
tangles formation. Ferritin immunohistochemistry demonstrated
widespread Microglial
cell proliferation, confirming further the generalized character of
CNS pathology in PSP
Yamada T, McGeer PL, McGeer EG (1992) Some
immunohistochemical features of argyrophilic grain dementia with
normal cortical choline acetyltransferase levels but extensive
subcortical pathology and markedly reduced dopamine.
J.Geriatr.Psychiatry Neurol. 5:3-13
Abstract: Detailed
immunohistochemical and biochemical studies are reported on two
cases of progressive dementia showing no Alzheimer-type pathology
but extensive argyrophilic grains as described previously by Braak
and Braak. These cases had no specific clinical features, and the
pathology of these brains showed subcortical gliosis (proliferation
of astrocytes and Microglia)
without significant neuronal losses. Interesting novel
immunohistochemical findings were the profuse appearance of
complement-activated oligodendrocytes and oligodendroglial
microtubular masses. Their appearance seems to indicate
oligodendroglial reactions to widespread damage of myelinated axons.
Cortical levels of choline acetyltransferase were normal, but
striatal levels of dopamine and its metabolites were markedly
reduced. This disease may be consistent with the criteria for
progressive subcortical gliosis
Jedrzejewska A, Dymecki J (1990) Intrastriatal grafts of
adrenal medulla in hemiParkinsonian
rats--ultrastructural study. Acta Neurobiol.Exp.(Wars.)
50:391-396
Abstract: The aim of the study was to investigate the
ultrastructure of the right striatum after intrastriatal adrenal
medulla grafts in Wistar rats with a 6-OHDA unilateral lesion of the
compact part of the right substantia nigra (SN). 12 adult rats were
investigated. Two rats were intact, 2 received a sham SN-lesion.
Ungerstedt's rotational test confirmed a significant lateral
SN-lesion in all the animals. Two weeks after the SN lesion small
samples of the adrenal medulla of 2-month old Wistar rats were
prepared (0.5 mm3) and implanted stereotaxically into the
middle-paraventricular region of the right striatum. The animals
were perfused with 2.5% glutaraldehyd according to the following
patern: 2--after 1 week of survival, 2--after 3 weeks, 2--after 6
weeks, and 2--after 3 months. 10 samples of ca 1 mm3 were taken from
3 regions of the right striatum (1) the region of the graft, (2) the
region in the neighbourhood of the graft, (3) tissue at a long
distance from the transplant. Macroscopic observation showed
granulomatous-like tissue at the place of the implantation of the
graft after 1 week of survival. After 3 weeks and later only the
evacuated cavity was observed instead of the graft. A routine
electron microscopic procedure was used to expose the material in a
JEM 100 B electron microscope. The study of the ultrastructure
indicated many leucocytes and Microglia
cells in the region of the graft as well as features of destruction
of the adrenal medulla cells in the rats perfused 1 and 3 weeks
after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Jellinger K, Paulus W, Grundke-Iqbal I, Riederer P, Youdim MB
(1990) Brain iron and ferritin in Parkinson's
and Alzheimer's diseases. J.Neural Transm.Park Dis.Dement.Sect.
2:327-340
Abstract: Semiquantitative histological evaluation of
brain iron and ferritin in Parkinson's
(PD) and Alzheimer's disease (DAT) have been performed in paraffin
sections of brain regions which included frontal cortex,
hippocampus, basal ganglia and brain stem. The results indicate a
significant selective increase of Fe3+ and ferritin in substantia
nigra zona compacta but not in zona reticulata of Parkinsonian
brains, confirming the biochemical estimation of iron. No such
changes were observed in the same regions of DAT brains. The
increase of iron is evident in astrocytes, macrophages, reactive
Microglia
and non-pigmented neurons, and in damaged areas devoid of pigmented
neurons. In substantia nigra of PD and PD/DAT, strong ferritin
reactivity was also associated with proliferated Microglia.
A faint iron staining was seen occasionally in peripheral halo of
Lewy bodies. By contrast, in DAT and PD/DAT, strong ferritin
immunoreactivity was observed in and around senile plaques and
neurofibrillary tangles. The interrelationship between selective
increase of iron and ferritin in PD requires further investigation,
because both changes could participate in the induction of oxidative
stress and neuronal death, due to their ability to promote formation
of oxygen radicals
McGeer PL, Itagaki S, Akiyama H, McGeer EG (1988) Rate of
cell death in Parkinsonism
indicates active neuropathological process. Ann.Neurol.
24:574-576
Abstract: It has been hypothesized that idiopathic
Parkinsonism might be due
to age-related attrition of dopamine neurons occurring long after an
initial acute episode. We present evidence against this hypothesis,
based on our finding of at least six times as many HLA-DR-positive
Microglia
phagocytosing dopamine neurons in Parkinsonian
brains as in control brains. This difference indicates an active
pathological process
McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive
Microglia
are positive for HLA-DR in the substantia nigra of Parkinson's
and Alzheimer's disease brains. Neurology 38:1285-1291
Abstract:
We detected large numbers of HLA-DR-positive reactive Microglia
(macrophages), along with Lewy bodies and free melanin, in the
substantia nigra of all cases studied with Parkinson's
disease (5) and Parkinsonism
with dementia (PD) (5). We found similar, but less extensive,
pathology in the substantia nigra of six of nine cases of dementia
of the Alzheimer type (DAT) but in only one of 11 age-matched
nonneurologic cases. All dementia cases with a premortem diagnosis
of DAT or PD showed large numbers of HLA-DR-positive reactive
Microglia
and significant plaque and tangle counts in the hippocampus, as well
as reduced cortical choline acetyltransferase activity. One of 11
nondemented controls showed mild evidence of similar cortical
pathology. These data indicate that HLA-DR-positive reactive
Microglia
are a sensitive index of neuropathologic activity. They suggest a
frequent coexistence of DAT- and Parkinson-type
pathology in elderly patients
McGeer PL, Itagaki S, McGeer EG (1988) Expression of the
histocompatibility glycoprotein HLA-DR in neurological disease. Acta
Neuropathol.(Berl) 76:550-557
Abstract: Reactive Microglia
or macrophages expressing the histocompatibility glycoprotein HLA-DR
were detected in many neurological diseases including Alzheimer's,
Parkinson's, Pick's and
Huntington's diseases, Parkinsonism-dementia
of Guam, amyotrophic lateral sclerosis, Shy-Drager syndrome,
multiple sclerosis and AIDS encephalopathy. Reactive astrocytes,
also present in these conditions, were established as a population
distinct from the HLA-DR positive Microglia
by double immunostaining for glial fibrillary acidic protein and
HLA-DR. A distinctive pattern of HLA-DR positive cells was seen in
each disease entity. Areas known to contain pathology always stained
positively, and, in several cases, reactive Microglia
appeared in areas that would otherwise not have been suspected of
being involved in the pathological process. HLA-DR staining, which
outlines the surface membranes of positive cells, was so strong that
lesioned areas could frequently be identified in sections with the
naked eye. In adjacent sections stained with H&E or sections
destained of HLA-DR and then restained with H&E, gliosis was
often hard to identify except on close microscopic inspection. The
results suggest that HLA-DR staining may be a valuable addition to
standard neuropathological methods and might be useful in
investigating diseases where pathology has not yet been identified